Update on carbohydrate-containing antibacterial agents

Review

10.1517/17460440902778725 © 2009 Informa UK Ltd ISSN 1746-0441 315All rights reserved: reproduction in whole or in part not permitted

Update on carbohydrate-containing antibacterial agents Georg Schitter & Tanja M Wrodnigg † Technical University Graz, Institute of Organic Chemistry, Univ.-Doz. TMW, Dip.-Ing. GS, Glycogroup, A-8010 Graz, Austria

Background : Since the first known use of antibiotics > 2,500 years ago, a research field with immense importance for the welfare of mankind has been developed. After a decrease in interest in this topic by the end of the 20th century the occurrence of (poly-)resistant strains of bacteria induced a revival of antibiotics research. Health systems have been seeking viable and reliable solutions to this dangerous and expansive threat. Objective : This review will focus on carbohydrate-containing antibiotics and will give an outline of recently published novel isolated, semisynthetic as well as synthetic structures, their mechanism of action, if known, and the strategies for the design of compounds with potential by improved antibacterial properties. Methods : The literature between 2000 and 2008 was screened with main focus on recent examples of novel structures and strategies for the lead finding of exclusively antibacterial agents. Results/conclusion : With the explanation of the role of the carbohydrate moieties in the respective antibacterial agents together with better synthetic strategies in carbohydrate chemistry as well as improvements in assay development for high throughput screening methods, carbohydrate-containing antibiotics can be used for the finding of potential drug leads that contribute to the fight against infections and diseases caused by (resistant) bacterial pathogens.

Keywords: aminocoumarin antibiotics , aminoglycoside antibiotics , antibiotics against endotoxins , carbohydrate-containing antibiotics , glycopeptide antibiotics , macrolide antibiotics , mono- and oligosaccharide antibiotics , nucleoside antibiotics

Expert Opin. Drug Discov. (2009) 4 (3):315- 356

1. Introduction

Antibiotics are bacterial or fungal metabolites that inhibit the growth of bacteria, fungi, protozoa or initiate their degradation and as such are used for the treatment of infectious diseases caused by these microorganisms. The first known application of antibiotics dates back to the Chinese, 2,500 years ago. On the basis of Pasteur’s description of antibiosis and Flemings’s discovery of the ‘miracle’ penicillin, a research field with immense importance for the health care of mankind as well as great commercial interest was created. With the big success of the treatment of tuberculosis, the plague, treatment of wounds and ulcers in World War II, gonorrhoea, pneumonia and a variety of other bacterial infections, the research devoted to antibiotics lost momentum because, apparently, these diseases were all thought to be under control and the problem seemed to have been solved. The extensive overuse and/or misuse of antibiotics in humans, animals as well as in agriculture, not only for treatment but also for prevention and prophylaxis of diseases together with failure in following the compliance, has led to bacterial species learning to defend themselves against conventional antibiotics. The development of resistant strains, which entailed a worldwide appearance and distribution of the mutant pathogens, has been the consequence [1-8] . Today, two million people die from tuberculosis each year. The awareness of resistance together with the understanding and explanation

1. Introduction

2. Glycopeptide antibiotics

3. Aminoglycoside antibiotics

4. Macrolide antibiotics

5. Nucleoside antibiotics

6. Antibiotics against endotoxins

7. Aminocoumarin antibiotics

8. Miscellaneous carbohydrate

antibiotics

9. Conclusion

10. Expert opinion

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Update on carbohydrate-containing antibacterial agents

316 Expert Opin. Drug Discov. (2009) 4(3)

of biosynthesis and metabolic pathways of the microorganisms reinduced a noteworthy revival of antibiotics research. Emphasis is laid on the improvement of existing drugs by chemical or enzymatic modification of known structures to create novel semisynthetic antibiotics against the rising danger of resistant strains and disease pattern. In this context car-bohydrate-containing antibiotics are thought to be versatile agents to deal with this problem [9,10] .

Carbohydrate-containing antibiotics are molecules of a variety of different structural compound classes. The sugar moieties can be part of the main structural feature, such as in nucleoside and aminoglycoside antibiotics, or be attached to a non-carbohydrate core structure, such as in macrolides, glycopeptides and aminocoumarines. Additionally, there are mono- and oligosaccharide compounds of more or less complex

assembling. With respect to their different structural features they choose from a large repertoire of targets in the bacterial biosynthesis machinery thereby functioning using different mechanisms of action ( Figure 1 ). Most important is the fact that the carbohydrate moieties present in antibacterial agents are very often exclusive in nature, and are not found in humans, which is an essential fact for selective targeting.

The explanation of the biosynthetic pathways of microor-ganisms using novel tools in genomics and proteomics and the high-resolution insights into the mechanism of action on the molecular basis of pharmacophores in their interaction with the respective target shed light on the role of carbohydrate moieties in antibacterial agents and is about to be understood in detail. However, in some cases the contribution of the sugar part still remains unclear. If the target of the agent involves

DNA/RNA replication

Aminocoumarines

DNA gyrase

RNA

50S

30SRibosome

Protein

Protein biosynthesis

GlcNAc

Cell wall biosynthesis

Aminoglycosides

RNA polymerase

MurNAc

MraYNucleoside antibiotics

tunicamycin

Glycopeptides

Moenomycinramoplanin

P

PP

UDP

UDP

Macrolidesevernimicin

P

PP

PP

Figure 1 . Principal mode of action of carbohydrate-containing antibiotics. Aminocoumarines: Inhibition of DNA-gyrase and topoisomerase IV. Nucleoside antibiotics and tunicamycins: Inhibition of the phospho-UDP- N -acetylmuramoyl-pentapeptide translocase (MraY). Macrolides, evernimicin: Inhibition of protein synthesis by binding to the 50S ribosome subunit and thereby blocking the translocation reaction. Aminoglycosides: Inhibition of the translocation of the peptidyl-tRNA by binding to the 30S ribosomal subunit. Ramoplanins and moenomycins: Inhibition of the cell wall peptidoglycan formation by binding to lipid II. Glycopeptide antibiotics such as vancomycin: Inhibition of transglycosylation by noncovalently binding to the peptidoglycan precursors terminating in a D -ala- D -ala sequence. Adapted from [11] .

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Expert Opin. Drug Discov. (2009) 4(3) 317

carbohydrate processing enzymes, or cell compartments such the cell wall, RNA or DNA, where carbohydrate residues are present, it is obvious that the sugar residues display the pharmacophore and that the carbohydrate part is intrinsically necessary for the interaction. In other cases, carbohydrate residues are attached to the effective active residue of the agent thereby being important for initiating the right biologically active conformation for the overall binding to the target. Furthermore, it was shown that carbohydrate components can be responsible for dimerisation effects of certain agents leading to an increased activity as a result of the multivalent effect. In general, sugar residues are hydrophilic components that contribute to a favourable pharmacokinetic profile of the agents such as absorption properties, bioavailability, stability, clearance and so on. However, there seems to be a reason why nature takes advantage of the presence of carbohydrate moieties in antibacterial compounds. We should learn to use this sweetness for our benefit by creating improved antibiotic agents to accomplish the problem of bacterial diseases.

This review gives an update on carbohydrate-containing antibiotics of the past decade. In this context, emphasis is laid on antibacterial agents exclusively. From a chemist’s point of view the article is basically organised by structure classes, namely, glycopeptide antibiotics, aminoglycoside antibiotics, macrolide antibiotics, nucleoside antibiotics, antibiotics against endotoxins, aminocoumarin antibiotics, monosaccharide and oligosaccharide antibiotics as well as miscellaneous structures.

2. Glycopeptide antibiotics

Glycopeptide antibiotics [12-14] consist of a cyclic peptide backbone with typically seven amino acid residues, representing atropisomerism by interlinkage of amino acid side chains, and show high activities against Gram-positive bacteria. The peptide backbone is O-glycosylated with different mono- or disaccharidic moieties at up to four positions. The binding to the target occurs through a set of peptide backbone contacts by means of hydrogen bonds between the D -ala- D -ala dipeptide and the amides that line a cleft formed by the cross-linked heptapeptide of the agent. This noncovalent binding to the peptidoglycan precursors terminating in a D -ala- D -ala sequence cause a steric impediment that prevents transglyco-sylation and cross-linking of the peptide side chains during peptidoglycan assembly [13,15,16] . The two most prominent and best-known representatives in this class are vancomycin ( 1 ; Figure 2 ), with the disaccharide D -glucose- L -vancosamine attached to the phenolic group of hydroxyphenylglycine at amino acid 4 of the heptapeptide and teicoplanin ( 5 ; Figure 3 ), which carries a more lipophilic N -acyl-vancosamine moiety and two extra sugar residues as well as minor modifications in the heptapeptide. They are the choice for empiric therapy and treatment for infections caused by Gram-positive bacteria and are often referred to as last-resort drugs because of their activity against bacteria that are resistant against many other antibiotics, especially MRSA [17,18] . Extensive use of vancomycin

and teicoplanin [19-23] in clinical practice [24] as well as the related avoparcin ( 2 ; Figure 2 ) [25] in agriculture triggered bacterial strains to protect themselves by changing the com-position of the target peptide portion. Modification by replacement of the terminal amino acid residue D -ala by D -lactate or D -serine causes a disturbance of the hydrogen-bond pattern during the interaction between the drug and the peptidoglycan and, therefore, led to a 1,000-fold decrease in affinity of glycopeptides [14,26] . In an urgent programme for developing a model to arm vancomycin against resistant strains, Williams has proposed that lipid substituents on vancosamine induce membrane localisation by anchoring and dimerisation of the drug at the target site. Both charac-teristics cause better binding to the D -ala- D -lac peptides [27] . Consequently, attempts have been made for the development of semisynthetic glycopeptide agents [28-31] by N-alkylation or N-acylation of the vancosamine moiety in vancomycin and related compounds [18,19,32-38] . Performing a solid- and solution-phase synthesis Nicolaou and coworkers have done several vancomycin libraries with molecular glycodiversity. Several highly potent compounds effective against vancomycin-resistant strains were obtained by this approach [39] . Furthermore, the conjugation of extra carbohydrate residues along the peptide backbone was introduced as modification strategy. For example, oritavancin (LY333328, 3 ; Figure 2 ) contains a p -chloro-phenylbenzyl substituent attached to the amino function of the disaccharide D -glucose-4- epi -van-cosamine as the main modification, thus providing both hydrophobic as well as hydrophilic groups. This lipoglyco-peptide demonstrates activity similar to vancomycin but possesses improved activity against vancomycin-resistant Staphylococcus aureus (VRSA) and Enterococcus (VRE) strains. The enhanced interaction of this N -alkyl analogue of vanco-mycin likely has arrived from a conformational change induced by the introduced side chain of the disaccharide, thereby influencing the binding pocket. Furthermore, the p -chloro-phenylbenzyl substituent enhances dimerisation and facilitates interactions with the bacterial cytoplasmic membrane and provides a prolonged half-life. Recently, a second mode of action was suggested for oritavancin, namely, the binding to the pentaglycyl bridging segment within the peptidoglycan matrix thus inhibiting transpeptidation [40] . This new parenteral semisynthetic antibiotic awaits the results of supplementary Phase III studies for the treatment of complicated skin and skin structure infections; a new drug application is about to be filed [41-46] .

Telavancin ( 4 ; Figure 2 ) [47] is a semisynthetic analogue of vancomycin, containing an N -decyl-aminoethyl vancosamine moiety and a negatively charged N -(phosphonomethyl)aminomethyl group bound to the peptide backbone. The antibacterial properties result from a dual mode of action, the common inhibition of the peptidoglycan synthesis as well as extra effective depolarisation of the bacterial cell membrane, thereby disrupting its functional integrity. Telavancin shows a broad-spectrum microbial activity including

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1: V

anco

myc

in: R

1 =

H, R

2 =

H, R

3 =

asn

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5 =

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6 =

NH

2, R7

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H, R

8 =

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Avo

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1 =

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2 =

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3 =

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8 =

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= H

, R3

= a

sn, R

4 =

leuc

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= H

, R6

= e

, R7

= H

, R8

= O

H4:

Tel

avan

cin:

R1

= H

, R2

= f,

R3

= a

sn, R

4 =

leuc

, R5

= H

, R6

= g

, R7

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H, R

8 =

H

OO

N H

H NN H

H N

R1O

O

NH

R4

OR

5

O

O

O

OO

HO

HO

OH

OO

R8

R6

HN

O -OO

C

OH

OH

HO

R3

Cl

Cl

R2

R7

H o

r C

l OH

O

OH

H2N

NH

2

O

O

NH

Me

leuc

asn

thyr

d

HN

Cl

eN H

PO

HH

O

Of

H NN

HC

10H

21

g

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OH

NH

2

a

Ris

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e

O

NH

Me

OO

OH

HO

OH

b

L-rh

amno

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HO

OH

OH

OH

c

D-m

anno

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4-ep

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OH

H2N

Van

cosa

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Fig

ure

2. S

tru

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res

of

van

com

ycin

(1)

, avo

par

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(2)

, ori

tava

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n (

3) a

nd

tel

avan

cin

(4)

.

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VRSA as well as MRSA and is effective in the treatment of soft-tissue infections, bacteremia, endocarditis, meningitis and pneumonia caused by Gram-positive pathogens. At present, this agent is undergoing review by the FDA for a new drug application [36,48-52] .

Another new lipoglycopeptide now awaiting full FDA approval is dalbavancin ( 6 ; Figure 3 ), a semisynthetic analogue of teicoplanin that shows a different glycosylation pattern with two O-linked monosaccharide residues, a 2- N -acyl- D -glucuronic acid instead of the vancosamine and an extra D -mannose at residue 7, as well as modifications in the C and N terminus of the peptide part. This compound follows the common glycopeptide mechanism of action, interaction with the terminal D -ala- D -ala feature as well as lipophilic anchoring in the bacterial membranes induced by the side chain attached to the glucuronic acid moiety. A tendency for dimerisation has also been reported. This agent provides

improved pharmacokinetic as well as pharmacodynamic properties, has a half-life of 170 – 210 h and an increased activity and superior efficacy in uncomplicated as well as complicated skin and skin structure infections. Dalbavancin is believed to benefit from the extremely long half-life allowing for weekly administration and is now undergoing another Phase III trial [53-58] .

Ramoplanins ( 7 ; Figure 4 ), lipoglycopeptides first isolated from Actinoplanes strain ATCC 33076 [59] , are different in structure and function compared to the vancomycin and teicoplanin families. They consist of a 49-membered macrocyclic depsipeptide containing 17 L- and D- amino acids and are O-glycosylated with an α -1,2-dimannosyl moiety. They are inhibitors of two enzymes involved in the late step of peptidoglycan biosynthesis. Ramoplanin binds to lipid II in a 2:1 stoichiometry, thereby inhibiting the extracellular transglycosylase-catalysed coupling of lipid II molecules to

O O

NH

HN

NH

HN

R2O

O

O

O

O

O

HN

O

R3

O

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Cl

R6

HO

HNH

O

R5

O

HO

O

O

R7HN

HO

OH

R8

OH

OH OH

OH

R1

R4

5: Teicoplanin A2: R1 = H, R2 = β-D-GlcNAc, R3 = COO-, R4 = H, R5 = NH2, R6 = Cl, R7 = C(O)-(CH2)6C(CH3)2, R8 = CH2OH6: Dalbavancin: R1 = H, R2 = H, R3 = a, R4 = Cl, R5 = NHMe,R6 = H, R7 = C(O)-(CH2)6C(CH3)2, R8 = COOH

O

AcHN

OH

OH

OH

N-acetyl-β-D-glucosamine

a

NH

N

O

Figure 3. Structures of teicoplanin (5) and dalbavancin (6).

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N H

O

H N

O

N H

O

O

OC

ON

H2

HN

O

HN

HN

O

HN

O

OH

OH

N

H N

O

O

NH

OH

O

H N

O

N H

NH

2

ONH

OHO

NH

O

HN

Cl

OH

OH N

OH

2N

O

OH

NH

2

OH

OH

O

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O

O

OH

OH

HOO

O

OH

HO

HO

HO

7: R

amop

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2

Fig

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4. S

tru

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res

of

ram

op

lan

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2 (7

) an

d m

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op

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myc

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(8).

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form the carbohydrate chain of glycopetidoglycans, which precludes maturation of the bacterial cell wall [60] . Ramoplanin was also found to directly inhibit MurG, an enzyme responsible for the conversion of lipid I to lipid II, although this transformation is intracellular and would require cell membrane penetration of the agent, a pathway actually not accessible for this compound. The dimannosyl group is not required for biological activity, but clearly accounts for the noncompetitive inhibition pattern. Ramoplanin factor A2 is now undergoing Phase III clinical trials as a promising broad spectrum drug candidate against Gram-positive bacteria including VRE and MRSA and, most importantly, no resistance has been observed as yet [61,62] .

Mannopeptimycin ( 8 ; Figure 4 ), isolated as a mixture of compounds from the strain Streptomyces hygroscopicus LL-AC98 [63] , is another class of cyclic hexapeptides with alternating D - and L -amino acids containing characteristic guanidine moieties, one of them carrying an N -linked D -mannose residue. Furthermore, these compounds are O-glycosylated with an isovaleryl modified dimannose residue. The presence of the hydrophobic acyl substituent at the terminal mannose is relevant for the activity. These lipoglycopeptides interfere with the later stage of bacterial cell wall biosynthesis by blocking the transglycosylation reaction mediated by binding to lipid II in a different mode of action compared to vancomycin. Mannopeptimycin

as well as several semisynthetic analogues obtained by chemical derivatisation show exceptional activity against multidrug-resistant pathogens such as MRSA and VRE and, therefore, clearly have potential as therapeutic candidates for clinical drugs [64-67] .

Ramoplanins as well as mannopeptimycin demonstrate that the blocking of transglycosylation reaction in Gram-positive cell wall biosynthesis by binding to lipid II is an alternative mechanism and a different target for microbial agents.

The role of the carbohydrate moieties of glycopeptide antibiotics still remains not fully explained yet. Removal of the sugar portion often decreased in vivo activity significantly indicating their high importance for the pharmacological profile of the antibacterial agents. In general the conjugation of carbohydrate moieties introduces hydrophilic character to a drug or biologically active molecule, which contributes to a favourable pharmacokinetic profile thereof and has a positive influence on its solubility as well as stability [68] . They may also be supportive for the initiation of the biologically active conformation of the peptide backbone for the interaction with the target. Furthermore, it was shown that carbohydrate components are responsible for dimerisation of the drug mono-mers leading to an increased intrinsic affinity of the dimer to their respective targets and, thus, increased activity of the pharmacophore as a result of the multivalent effect [69] .

Figure 4. Structures of ramoplanin A2 (7) and mannopeptimycins (8) (continued).

HN

HN

HNNH

NH

NH

O

O

O

O

O

O

NHHN

NH

H

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H

OHN

HN

HN

O

OH

OH

OH

OH

H

O

O

O

HO OH

HO

HO

O

OR

OR

OR

HO

8: Mannopeptimycin withR = H or

O

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Further hydrophobic moieties attached to the sugar help anchoring to the plasma membrane leading to an increase of drug concentration at the site of transglycosylation. It can be expected that there will be a continuous extension of the list of antibacterial glycopeptides by continuing screening programmes of novel semisynthetic compounds of known structures. Also, further explanation of the biosynthetic gene cluster of natural glycopeptide agents will provide a better understanding and more information, and will open possibilities to design unnatural analogues with advanced properties against drug-resistant pathogens by metabolic engineering [64] .

3. Aminoglycoside antibiotics

Aminoglycoside antibiotics are cationic molecules consisting of a six-membered aminocyclitol core structure, most commonly 2-deoxystreptamine (2-DOS) besides other central cyclitols such as streptidine, actinamine and fortimicin. The central unit is O-glycosylated with a varying number of different carbohydrate moieties. Most aminoglycosides are produced by Streptomyces and various Actinomycetes strains [70-74] . Streptomycin was the first antibiotic found to be active against Mycobacterium tuberculosis (MBT). So far, after 60 years of successful use of many compounds of the amin-oglycoside family, they remain powerful antimicrobial agents against Gram-negative as well as Gram-positive pathogens. The two most common structure types differ in the number of carbohydrate moieties bound to the core moiety 2-DOS: kanamycins ( 9 ; Figure 5 ) and gentamicins ( 10 ; Figure 5 ) carry two aminosugars whereas the neomycin family ( 11 ; Figure 5 ) is glycosylated with one mono- and one disaccharide resi-due. Apramycins ( 12 ; Figure 5 ), a third representative, contain a unique glycosylated bicyclic pyrano-pyrano core moiety and are used for veterinary medicines only [75] .

The mode of action of aminoglycosides as antibacterial agents has been investigated extensively and most thoroughly, recently by NMR analyses [76] and X-ray crystallography [77] . Their main molecular target is the A-site of bacterial 16S rRNA in a pocket of proteins of the small 30S subunit of the 70S prokaryotic ribosome [78,79] . Aminoglycosides provide hydrogen-bond donors with a preorganised 1,3-hydroxyamino feature represented along the carbohydrate scaffold as well as the 1- and 3-amino groups of the 2-DOS residue necessary for interaction with the highly conserved nucleotides in the RNA target. The binding creates a pocket because of mismatched A-A base pair and a single adenine induces a conformational change thereby stabilising the tRNA–A site complex. This in turn precludes efficient proofreading leading to reduced translational fidelity and aberrant proteins, which accumulate and compromise the integrity of the bacterial envelope, allowing for an increased uptake of aminoglycosides, which means progression in the misreading, and, finally, cell lysis occurs [70-73,80] . The impor-tance of the carbohydrate moieties with the participation of the bidentate 1,2- and 1,3-hydroxyamines of aminoglycoside

antibiotics and the rigidity of the functional groups is mirrored by the crystal structure of the RNA–aminoglyco-side complex. The neamine core, for example, contributes six direct or water-bridged H-bonds to phosphate oxygen atoms of adenosine 1492 and 1493 of the A-site. Addition-ally, up to a dozen direct and water-bridged H-bonds are formed to other base pairs and C-H- π interactions are devel-oped, clearly indicating the importance of the correct spatial arrangement of the H-donors in the aminoglycoside prompted by their conformation [81,82] . In general, the specific contacts with nucleotide residues are distinct between bacteria and humans, which is crucial for the selectivity of decoding site-binding antibacterial agents. Aminoglycosides are still leading drugs for the treatment of serious respiratory infections, and for other diseases such as septicaemia, complicated intra-abdominal infections, bacteraemia, endocarditis as well as complicated urinary tract infections. Again extensive (mis)use and insufficient compliance together with exposure through the animal foods we eat caused the development of resistance, enzymatic modification of the drug by the patho-gens playing the most important role for this type of anti-bacterial molecules [1-8,79,83,84] . The density of hydroxy- and aminogroups provides an ideal environment for modifying enzymes such as aminoglycoside acetyl transferases (AAC) leading to N-acetylation, adenosyltransferases (AAD or ANT) accomplishing O-nucleotidylation as well as phosphotrans-ferases (APH) responsible for O-phosphorylation reactions. Hence, multidrug-resistant S. aureus and Staphylococcus epidermidis strains have developed. Another successful strategy of bacteria is to decrease the uptake of aminoglycosides by energy-dependent efflux induced through mutations in components of the transmembrane transport system. Modification of the 16S rRNA target site by mutation or nucleotide methylation as well as alteration of the 30S ribosomal subunit target has also been observed but are rather rare mechanisms for resis-tance development [1,2] . These resistances, poor oral admin-istration associated with the high polarity of aminoglycosides as well as their relative toxicity [85,86] , such as nephrotoxicity, ototoxicity and reversible renal impairment, laid emphasis on the synthesis of modified aminoglycosides that provide higher binding affinity to RNA, better selectivity, better antimicrobial activity as well as stronger hardiness of the agents against modifying enzymes. The finding of new struc-tures to circumvent the resistance problem is focused on the assembling of semisynthetic analogues of natural aminogly-cosides because successful interaction is dependent on the presence of the conserved scaffolds of aminoglycosides. Different strategies were introduced such as the rational design by structure–activity relationship (SAR) studies as well as computer-aided information, combinatorial approaches to semisynthetic libraries of mimetics, attachment of the same or different aminoglycosides leading to homo- or heterodimeric structures, design of twin-drug conjugates or tethering of lipophilic moieties to the agents. An excellent review [87] gives an overview of systematic modification on aminoglycosides

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9: Kanamycin A 10: Gentamicin C1

O

O

O

O

O

HO NH2

NH2

H

OH

HN

HO

OH

H2N

H

OH

H2N

OH

12: Apramycin

O O

O

O

O

O

OH

NH2

NH2

HO

HO NH2

OH

OH

H2N

OH

HO

NH2

NH2

11: Neomycin B

OH NH2

O O

O

O

OH

HO

NH2

NH2HO

NH2

HO

HO

OH

2-DOS

H2N

HO

O O

O

O

OH

NH

NH2

HO

NH2

HN

2-DOS

2-DOS

2-DOS

Figure 5. Structures of kanamycin A (9), gentamycin C1 (10), neomycin B (11) and apramycin (12).

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classified according to the individual rings systems in the neomycin ( 11 ) as well as the kanamycin ( 9 ) systems. Additionally, modifications along the sugar rings with various different aromatic, heteroaromatic as well as cyclic and acyclic aliphatic substituents, introduction of polyfunctional moieties, ionisable groups as well as fluorescent dyes have also been done. The evaluation of the antibacterial behaviour of such semisynthetic structures puts the contribution of each individual sugar ring to the overall binding events of aminoglycosides into account. For example, the rigidity of the 2-DOS scaffold was found to play an essential role in the potency of aminoglycosides, as every single derivative replacing 2-DOS with a more flexible acyclic scaffold showed a clear decrease in activity [88] . In contrast to these findings, the azepane-glycoside derivatives ( 13 ; Figure 6 ), seven-membered ring struc-tures wherein a substituted heterocycle mimics the unique special arrangement of the conserved 2-DOS scaffold, showed target binding and inhibition of the growth of S. aureus including aminoglycoside-resistant strains [89] . Another approach is based on the findings that neamine binds to the oligonucleotide in the A-site in a 2:1 stoichio-metric fashion. Consequently, various symmetrical as well as asymmetrical dimers of neamin, such as compound 14

( Figure 6 ), nebramine and deoxystreptamine coupled by means of a flexible linker, were synthesised. Some examples were found to possess increased antimicrobial activity. It turned out that the length of the linker and its substituents are crucial determinants of the antibacterial activities of such bivalent aminoglycosides. Additionally, the dimers show inhibitory properties against bifunctional APH(2’’)-AAC(6’) aminoglycoside-modifying enzyme resistance [90-92] .

On the basis of the known role of the highly basic and planar guanidine group at many RNA–protein binding interfaces, guanidinylation of kanamycins, tobramycin, neo-mycin B as well as paromomycin was performed as another strategy for aminoglycoside modification. Such guanidino-glycosides ( 15 ; Figure 7 ) show increased activity and better selectivity compared to the parent structures [93] . In this context, arginine- and lysine-neomycin B conjugates (com-pounds 16 and 17 , respectively; Figure 7 ) were synthesised to investigate the contribution of side-chain length, flexibility and composition for the inhibitory potency of amino acid additives. The argininylated and guanidinylated neomycins showed efficient cellular uptake [94] .

Following the same idea, aminoglycoside–lipid conjugates were synthesised. Such cationic lipids are believed to facilitate

O O

NH2

OH

HO

H2N

HN

NH2

H2N

13

O

O O

HO

N N

OH

O O

O

HO

H2N

NH2

HO

H2N

OHHO

NH2

OH

H2N

NH2

OH

NH2H

2N

14: OPT-11

Figure 6. Structures of an azepane-glycoside analogue (13) and OPT-11 (14).

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R1 =

NH

NH2

NH2

C

O

NH

CNH

2

NH

NH2

O

NH2

O NH

NH2

O O

O

O

O

O

OH

NHR1

NHR1

HO

HO NHR1

OH

OH

R1HN

OH

HO

NHR1

NHR1

Neomycin analogues

Neamine

19: Locked neomycin derivative

O

O

OO

O

O

HO

NH2

H2N

HO

HO

OH

OH

NH

HO

NH2

NH2

NH2

15: R = OH, R1 =

16: R = OH, R1 =

17: R = OH, R1 =

18: R =

Figure 7. Structures of neomycin analogues (15 – 18) and locked neomycin (19).

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their transport through membranes. Particularly neomycin-C 16 as well as neomycin-C 20 conjugates ( 18 ; Figure 7 ) showed activity against multidrug-resistant strains including MRSA and MRSE possibly because of an improved uptake, changes in mode of action and enhanced affinity to RNA [95] .

Rational drug design has led to a great variety of semisynthetic aminoglycosides by derivatisation of natural compounds such as deoxygenation, epimerisation, N-alkylation, N-acylation, gly-cosylation, modifications at positions N-1 as well as O-6 and the like with the intention to improve the antibacterial properties of the parent compounds [87,96-104] . One important concern of modification is to cut down the structure of the agent to the essential principle that retains the activity of the parent compound by varying numbers of ring motifs and functional groups. Structural studies have revealed that the neamine unit is the minimal core structure required for RNA base recognition [104] . Conformational comparison of the aminoglycoside–RNA complex with the complex of the aminoglycoside and bacterial defence proteins led to the design of conformationally constrained neomycin ( 19 ; Figure 7 ) and paromomycin analogues. A covalent bond between two individual rings was introduced equivalent to the hydrogen bond of the parent compound in the ribosome-bound state. Thus, the conformation of the usually inherent flexible glycosidic bonds is restricted in this area, which provides an effective protection against aminoglycoside inactivation by ANT4, while maintaining a reasonable affinity for the interaction with ribosomal target-RNA. This finding proves that the difference showed by the restricted conformation within the binding pockets of the ribosome and of the enzymes involved in bacterial resistance can be used as strategy for the design of novel aminoglycosides with improved activity [105-107] .

Recently, heterologous expression, the production of aminoglycosides in non-aminoglycoside producing microor-ganisms, was introduced as entry for the search for new agents [108-111] . But only a few biosynthetic clusters have been cloned and expressed in hosts and very little informa-tion on the genetics of aminoglycosides production and its regulation is known thus far. However, genetic manipulation of the biosynthetic pathways based on the explanation of the gene clusters will clearly be supported by the under-standing of biosynthetic patterns and genetics of aminogly-coside producers and is strongly believed to provide another tool for the important discovery of new antibacterial struc-tures with improved activity via combinatorial biosynthesis protocols [112-114] .

4. Macrolide antibiotics

Macrolide antibiotics consist of 12-, 14-, 16- or 18-membered polyhydroxy lactones that are O-glycosylated at least at one position, usually with cladinose or desosamine and sometimes with other different deoxy- or aminodeoxysugars [115-117] . They have a broad spectrum of antimicrobial activity and are used as oral agents for the treatment of lower and upper respiratory

tract infections and have been applied for almost 60 years because of their safety and efficacy. More than 500 represen-tatives are known, most of them showing excellent behaviour as agents against Gram-positive bacteria. Their mode of action follows the inhibition of protein biosynthesis by binding exclusively to segments of 23S RNA of the 50S subunit of the bacterial ribosome, thereby preventing elongation of the growing peptide chain by blocking transpeptidation/translocation reactions. Some analogues can also inhibit mRNA translation at the level of the 23S rRNA [118] . Erythromycin ( 20 ; Figure 8 ), the most prominent representative, was the first compound on the market for the treatment of infections caused by β -haemolytic Streptococci and Pneumococci as well as for the treatment of patients allergic to β -lactam antibiotics. Rapid dispersal of resistant strains against macrolide agents occurred via typical bacterial mechanisms such as efflux pump changes and hydrolysis of the drugs, which is a serious and expanding problem. Specific mechanisms such as the disarming of these antibacterial agents by methylation of the 23S rRNA target caused by an adenine-specific N -methyltransferase (methylase) encoded by the erm family of genes, and, less often, modification of antibiotics through esterase and/or phosphotransferase activity have been observed. Furthermore, base pair mutations and ribosomal protein modifications were reported. In general, traditional macrolides are only poorly absorbed and lose their activity fairly fast under physiological acidic conditions by hydrolysis and deg-radation. Consequently, similar to the aforementioned anti-bacterial agents, modifications of the known macrolide families were explored as a strategy to deal with the resistance problem [119] . For example, 8,9-anhydroerythromycin A 6,9-hemiketal analogues ( 21 ; Figure 8 ), wherein the cladinose at position O-3 is replaced by a propynyl or triazole group, showed interesting activities against MRSA and VRE bacterial strains [120] .

Ketolides, semisynthetic analogues of erythromycin, are a next generation of macrolide antibiotics. They show excel-lent activities against many pathogens, especially macrolide-resistant Streptococcus pneumoniae . This compound class contains a keto group replacing the cladinose sugar moiety at position C-3, a cyclic carbamate at C-11 and C-12 and a heterocycle attached with a tether to a nitrogen or an oxygen of the macrolide. The length of this tether was found to be crucial for this interaction. The absence of the cladinose is responsible for the lack of erm inducing, the cyclic carbamate plays an important conformational role and the aryl rings pick up a further contact with ribosome at A752 in domain II. In general, ketolides are less suscep-tible to efflux in S. pneumoniae [121-124] . In 2004 telithromy-cin ( 22 ; Figure 9 ) was the first ketolide antibiotic that was approved and has been used for the treatment of pneumonia, acute exacerbation of chronic bronchitis and acute bacterial sinusitis [125,126] . Recently, studies indicated rare but severe side effects, which caused the restriction to community-ac-quired pneumonia by the US FDA, and caution in patients at

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O

OO

OR

O

HO

HO

O

N

HO

21: 8,9-anhydroerythromycin A 6,9 hemiketal analogues

R = cladinose, NR

N N

O

O

OH O

O

O

HO

HO

O

O

N

HO

OMe

OH

Desosamine

Cladinose

20: Erythromcin

Figure 8. Structures of erythromycin (20) and its 8,9-anhydroerythromycin 6,9-hemiketal analogue (21).

O

O

OR

O

OO

O

NHOO

R1

NO

N

NN

N

22: Telithromycin R = CH3, R1=

23: Cethromycin R1 = H,R=

Figure 9. Structures of telithromycin (22) and cethromycin (23).

risk has been advocated by European authorities. Very soon after its approval, telithromycin-resistant S. pneumoniae appeared, featuring a mutation in the 23S rRNA of the drug binding site demonstrating the explosive development of the resistance problem [127,128] . Cethromycin ( 23 ; Figure 9 ), yet another semisynthetic ketolide carrying the heteroaromatic moiety at position O-6, binds to the 50S ribosomal subunit by interfering with 23S rRNA of domains II as well as V and additionally prevents the construction of the 30S and 50S subunits. This ketolide is now undergoing Phase III trials for the treatment of community-acquired pneumonia and acute bacterial sinusitis [129-131] .

EDP-420 ( 24 ; Figure 10 ), a third generation analogue of erythromycin with a bridged bicyclic macrolide core structure was found to show an improved pharmacological profile compared to telithromycin and cethromycin, including activity against macrolide-resistant Streptococci as well as MRSA and VRE. This compound has a long half-life and is now undergoing Phase II clinical trials [132,133] . In relation to compound 24 structure 25 , a macrolide featuring a 3,6-bicyclic oxime was designed. The E isomers of 25 showed excellent antibacterial profiles against a broad spectrum of resistant pathogens [134] . The class of semisynthetic azalide macrolides contain a nitrogen atom inserted into the

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macrolactone aglycon introducing an aminolactone feature. These compounds are of increasing interest because of their advantageous pharmacokinetics, metabolic stability, high tolerability and low toxicity. The first azalide antibiotic on the market was azithromycin ( 26 ; Figure 10 ), which showed a secondary binding site directly interacting with the ribosomal protein L4 [123] . Its scaffold, featuring an amino and several hydroxy groups, led to the synthesis of a series of new compounds with advantageous pharmacokinetic properties [135,136] .

Tiacumicins are a group of 18-membered macrolide antibiotics isolated from cultures of Dactylosporangium aurantiacum . Tiacumicin B ( 27 , OPT-80, lipiarmycin, PAR-101; Figure 11 ), the main component produced in this culture, contains an

unsaturated macrolide core with an unusual C-5-methylated sugar at position C-11 and an aryl substituted 6-deoxy sugar moiety at C-20. This agent inhibits bacterial DNA-depen-dent RNA polymerase by blocking the formation of the first internucleotide bond. It showed broad-spectrum Gram-posi-tive antibacterial properties, is highly active against Clostridium difficile associated diarrhoea in low concentrations and is now undergoing Phase III trials [137,138] .

Recently, seven compounds named bispolides ( 28 ; Figure 11 ) have been isolated from a culture of Microbispora sp. Their core was found to be a symmetric cyclic dimeric structure of a novel unsaturated 20-membered ring macrolide that is glycosylated with 2,6-dideoxyhexopyranose and 6-deoxyhexopyranose

O O O

N

HO

O

NNN

O O

HO O O

N

N

24: EDP-420

O O O

N

HO

O O

O

HN

O

O

O

N

(CH2)n

O

25: 3,6-Bicyclolide oxime derivatives n = 0-5

O

N

OH

OO

HO

OH

O

OO

N

HO

OH

MeO

26: Azithromycin

O

Figure 10. Structures of EDP-420 (24), 2,6-bicyclolide oxime derivative (25) and azithromycin (26).

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O

O

OH

OHO

O

O

OH

O

HO

O O

O

OH

O

O OH

Cl

OH

Cl

OO

O

OH

O

OO

O

HO

O

OO

R2O

OH

OH

OR1

HO

OH

R3

27: Tiacumicin B

28: Bispolide B2a: R1 = H, R2 = Me, R3 = OH

Figure 11. Structures of tiacumicin B (27) and bispolide B2a (28).

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alternatively. These structures turned out to show good anti-MRSA activities in vitro [139] .

Macrolide antibiotics have been investigated extensively over the past decade driven by the success of telithromycin. However, the significance of the carbohydrate moiety in macrolide agents still remains unclear; no direct interaction with the ribosome could be observed by X-ray studies thus far. In general, modifications on the macrolide aglycon remain manageable using smart and creative chemistry, the synthesis of semisynthetic analogues with differentiation in the sugar moiety remains a very difficult task, chemical manipulations of deoxysugars are extremely challenging. One approach to introduce glycodiversity to the macrolide system is to manipulate the sugar machinery to obtain a change in the glycosylation pattern, which seems to be crucial for the antibacterial activity. This strategy is expected to allow for an alteration of the pharmacological and pharma-cokinetic behaviours of the agents. However, such a fine tuning of microorganisms is an ambitious project that has been described recently for macrolide antibiotics [140] . Modern methods of structural analysis in combination with the advances in molecular biology now allow the determination of the structures in their solid-state conformations. This information in combination with computational methods may help to identify hit and lead structures by simple modification of the chemical structure to obtain key pieces of information about the binding mode, as could be shown previously for macrolides antibiotics [141] .

5. Nucleoside antibiotics

Nucleoside antibiotics [142,143] are found in a large structural variety featuring nucleosides in conjugation with other components such as peptides, lipids, extra carbohydrate moieties and many more, sometimes unusual compositions. The nucleoside core of these agents is usually an aldofuranose moiety N-linked to a heterocyclic base. This structural feature already indicates their potential for interacting and interfering with RNA and DNA and the related enzyme machinery, which results in a variety of biological activities such as antibacterial, antifungal, antitrypanosomal, antitumour, antiviral, herbicidal, insecticidal, immunostimulating as well as immunosuppressive properties. This chapter handles nucleo-side antibiotics that show bacterial interactions, wherein the sugar component as part of the nucleoside moiety counts for the term ‘carbohydrate-containing’ antibiotic.

5.1 Inhibition of MraY The bacterial enzyme phospho-UDP- N -acetylmuramoyl-pentapeptide translocase (MraY, translocase I) catalyses the formation of lipid I by transferring the UDP-MurNAc moiety to undecaprenyl phosphate, which is a carrier molecule embedded in the cytoplasmic membrane. This protein is a well-recognised target of nucleoside antibacterial agents such as several lipido and peptidyl nucleosides [144-146] .

Tunicamycins ( 29 ; Figure 12 ) [147,148] , produced by several Streptomyces sp., are composed of an uracil moiety, a N -acetyl- D -glucosamine residue and an unique 11-carbon dialdose sugar called tunicamine that carries an amide-linked fatty acid residue at the amino function. Representatives of this compound class are known to be substrate analogue inhibitors of MraY but lack selectivity [149] . In eukaryotes, tunicamycin blocks the first step of protein N-glycosylation by inhibiting dolichol phosphate GlyNAc-1-P transferase, thereby mimicking the transferred GlcNAc-1-phosphate and, thus, causing toxicity. Other more specific MraY inhibi-tors within this class, such as caprazamycins, muraymycins, riburamycins and capuramycins, were found to show promising profiles and broad-spectrum antibacterial activity, including relevant resistant strains and in vivo efficacy without toxicity. Capuramycins ( 30 ; Figure 12 ), uracil nucleosides having an unsaturated uronic acid moiety connected by means of an amide linkage to a caprolactame residue, demon-strated rapid bacterial activity against several different mycobacterial species by inhibiting translocase I [150,151] . Caprazamycins and liposidimycins ( 31 and 32 , respectively; Figure 12 ) contain an uridine moiety substituted at O-5' with a 5-amino-5-deoxyribose, liposidomycins are sulfatet at position O-2. Additionally, the uridine moiety carries a characteristic 1,4-diazepan-3-one heterocycle at position C-5' which is linked to lipophilic side chains [152] . Liposidomy-cins selectively inhibit bacterial translocase I in vitro . The hydrophilic sulfate group at C-2" may cause poor permeability and, therefore, less antimicrobial activity than expected. This was actually observed in studies with liposidomycin structures lacking the sulfate group at this position [145] . Recently, it was shown that the lipophilic side chains interact with a highly hydrophobic trans -mem-brane domain of MraY [153] . Caprazamycins additionally contain a per- O -methylated fucosyl residue. The individual members of this class are distinguished in their lipid side chains. This compound class has shown excellent antimyco-bacterial activity in vitro against drug-susceptible and multidrug-resistant MBT strains without significant toxicity in mice [154,155] . To break down the complexity for liposidomycins and caprazamycins, acyclic analogues were designed and synthesised [152,155] . These compounds were expected to be promising leads for anti-tuberculosis agents such as the semisynthetic CPZEN-45 [156] , a 4-butylaniline amide derivative of caprazamycins. Mureidomycins ( 33 ; Figure 12 ) are peptidyl nucleosides produced by Streptomy-ces flavidovirens and contain a 3'-deoxyuridine sugar attached by means of an enamide linkage to a peptide chain containing two meta -tyrosine residues, one methionine residue and an N -methyl-2,3-diaminobutyric acid moiety. This class also selectively and specifically inhibits bacterial translocase I and, most importantly, does not inhibit mammalian polysaccharide or glycoprotein synthesis and, therefore, benefits from very low toxicity [157] . With a solid-phase synthesis, a simplified uridinyl branched peptide urea

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O

HO OH

O

O

HN

HO

OH

O

HN

OH

OH

OH

OO

(CH2)8–11

HO

N

HN

O

O

29: Tunicamycin

R2O N

NHO2C

O

O

O N

NH

O

HO OH

R1O

HO NH2

O

O

31: Caprazamycin BR1 = H, R2 =

O

O

O

O

OO

OMe

MeO OMe

32: Liposidomycin B R1 = SO3H, R2 =

OCO

2H

O

O

7

Tunicamine

O

O

OR

N

HNO O

MeO

OO

OH

OH

HN

O

HN

O

O

C12H2530: Capuramycin R = H analogues R =

NH2

Figure 12. Structures of tunicamycin (29), capuramycin (30), caprazamycin B (31), liposidomycin B (32), mureidomycin A (33), muraymycin A1 (34).

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library with structural similarity to the mureidomycin class was obtained, of which a high throughput screening identi-fied several compounds with moderate anti-tuberculosis activity [158] . In the same context, a thymidinyl diepeptide urea library with three points of diversity and a 2'-deoxyu-ridinyl Ugi library with four points of diversity were designed to obtain peptidyl nucleoside analogues. Both libraries were screened for anti-tuberculosis activity showing active hit structures [159,160] . Muraymycins ( 34 ; Figure 12 ) are structur-ally and mechanistically related to uridyl antibiotics such as mureidomycins, and have a common peptide-appended glycosylated uronic acid core structure. They are also MraY inhibitors. A series of muraymycin analogues were synthesised and evaluated in a SAR study whereby some derivatives showed excellent antimicrobial activities [161,162] .

5.2 Miscellaneous nucleoside antibiotics Sansanmycin ( 35 ; Figure 13 ), a nucleosidyl peptide antibiotic similar to mureidomycins, recently isolated from an unidentified Streptomyces sp. SS., was found to show specific inhibitory activity against Pseudomonas aeruginosa and MBT H 37 Ra as well as against multidrug-resistant strains of MBT [163] .

It is known that unnatural pyrimidine nucleosides can specifically target the mycobacterial enzymes involved in DNA and RNA synthesis. In this context, the synthetic 1- β - D -2’-arabinofuranosyl and 1-(2’-deoxy-2’-fluoro- β - D -2’-ribofuranosyl) pyrimidine nucleoside analogues ( 36 ; Figure 13 ) were found to have potent antimycobacterial properties and showed also activity against drug-resistant MBT [164] . The same research group examined 2'-3'-dideoxyuridin analogues with alkyl and alkynyl substituents at position C-5 ( 37 ; Figure 13 ) and found

Figure 12. Structures of tunicamycin (29), capuramycin (30), caprazamycin B (31), liposidomycin B (32), mureidomycin A (33), muraymycin A1 (34) (continued).

HO2C

HN

HN

NH

HN

O

SMe

OMeN

O

NH2

HO

HO O

O

OH

NH

O

O

33: Mureidomycin A

34: Muraymycin A1

HN

HN

NH

HN

HN

OHHO

O

OHN

NH

HN

OO

O

O

O N

OHHO

O

NH

O

O

O

OHHO

H2N

ON NH

2

11

NH

OH

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O NHO

HN

O

O

CxHy

R2

R1

36: R1 = F, R2 = OH, x = 10;11, y = 21;2337: R1 = R2 = H, x = 10;11, y = 21;2335: Sansanmycin

NH

HN

NH

O

N

OH

2N

OH

O

S

NH

HO2C

O

HN

ON

NH

O

O

OH

Figure 13. Structures of sansanmycin (35), 1-(2’-deoxy-2’-fl uoro-β-d-2’-ribofuranosyl) pyrimidine nucleoside analogue (36) and 2’,3’-dideoxyuridin analogue (37).

compounds that show marked inhibitory activity against Mycobacterium bovis and MBT. In addition, the compounds inhibited the growth of selected Gram-positive bacteria in vitro and showed low cycotoxicity. Thus, they are believed to be potential clinical candidates for the treatment of tuberculosis [165] .

Several 1,3-thiazolidine pyrimidine nucleosides modified at position 5 ( 38 ; Figure 14 ) were found to be active against common human Gram-positive pathogens. Therefore, they were thought to be good leads for further investigation of the therapeutic value of this substance class. They bind to the bacterial 50S ribosomal subunits thereby inhibiting the formation of the 70S initiation complex [166] .

Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), essential for providing the organism with deoxythymidine triphosphate, was recently considered as available target for the design of a novel class of anti-tuber-culosis agents. A series of synthetic bicyclic thymidine derivatives ( 39 ; Figure 14 ) was synthesised and their activity investigated in a SAR study, wherein most compounds were found to inhibit growth of MBT confirming TMPKmt as attractive target for further inhibitor design [167] .

The andenylate-forming enzyme (MbtA) is a protein along the biosynthetic pathway of mycobactins, the iron chelating growth factors produced by MBT for its iron acquisition. MbtA first activates salicylic acid at the expense of ATP to form salicyl-adenylate and then binds the phosphopantheine co-factor of the thiolation domain and transfers the acyl adenylate onto the nucleophilic sulfur. By replacing the labile acyl phosphate function by a rather stable sulfonamide,

the rationally designed adenosine nucleotide compounds ( 40 ; Figure 14 ) mimic the tight binding of the acyl adenylate intermediate by incorporation of stable linkers as bioisosters. These compounds are classified as bisubstrate inhibitors or intermediate mimetics [168] . In this context, β -ketosulfonamide adenylation inhibitors have been synthesised [169] .

S-Adenosyl- L -homocysteine (SAH) is the substrate for SAH nucleosidase in bacterial methionine salvage pathway that catalyses the conversion of methylthioadenosine into methylthioribose and adenine. This protein is not found in humans and, consequently, potential inhibitors should be non-toxic for humans. Structures such as 1,3-dideazaadenosine ( 41 ; Figure 14 ) are similar to SAH and, therefore, studies of their inhibitory potential on SAH nucleosidase are under investigation [170] . SAH nucleosidase transition state structure mimicking iminosugars such as adenosine analogue 42 ( Figure 14 ), which are substituted at position S-6 as well as methylene-bridged hydroxypyrrolidines, were found to show activities against Escherichia coli SAH nucleosidase down to the picomolar molar range [171] .

A common strategy for the development of new compounds in the nucleoside class is the design of novel sugar moieties by replacing the ring oxygen with heteroatoms such as nitrogen, sulfur, phosphorous, emplacing a carbacycle or changing of ribose to alternative heterocyclic systems. A complementary approach is to identify the pharmacophore of known complex nucleoside antibiotics and emphasise further synthetic modifications on this scaffold to obtain structures with advantageous properties [172] .

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S

HN

NHO

NH

O

OBr, Cl

38: 1,3-Thiazolidine pyrimidine analogue

ON

NH

HN

O

S

O

O

39: Bicyclic thymidine analogue 40: Salicyl-sulfamate analoguse, R = OH, NH2, H

RS

HO OH

O

N

N

NH2

41: 1,3-Dideazaadenosine R = CH2CH2COOH, CH2CH2COOEt

N

NH2

N

N

N

HO

S

Cl

42: 9-Deazaadenine-hydroxypyrrolidine analogue

ON

HO OH

N

N

N

NH2

OS

O

NH

OOR

Figure 14. Structures of 1,3-thiazolidine pyrimidine analogue (38), bicyclic thymidine analogue (39), salicyl-sulfamate analogues (40), 1,3-dideazaadenosine (41) and 9-deazaadenine-hydroxypyrrolidine analogues (42).

Many examples of nucleosides antibiotic structures show promising activities against several bacterial strains and, thus, have great potential for antibacterial agents. However, they suffer from disadvantages such as poor adsorption by oral administration, chemical lability, complexity as well as mod-erate cell entry ability. Furthermore, considering that the DNA as well as RNA machinery works essentially with the same molecules found in all organisms including humans, one main disadvantage of nucleoside antibiotics is the lack of selectivity and cross-activity in mammalian cells. Hence, so far, no nucleoside antibiotic agent is in clinical use for antibacterial treatment.

6. Antibiotics against endotoxins

This group of carbohydrate-containing antibacterial agents target the biosynthesis of lipopolysaccharides (LPS, endotoxins, 43 ; Figure 15 ), the membrane bound structural building block of the Gram-negative bacteria envelope. Lipopolysaccharides consist of three structural sections, lipid A ( α -1- β -6 linked GlucNAc-disaccharide carrying two phosphates at positions O-1 and O-4' as well as a variable number of fatty acids), the core oligosaccharide built up of 3-deoxy- D - manno -octulosonic acid ( 44 ; Figure 15 , KDO) and L - glycero - D - manno -heptose ( 45 ;

Figure 15 ) units as well as the O-antigen, a repeating oligo-saccharide of various carbohydrate moieties such as D -glucose, D -galactose, N -acetyl- D -glucosamine, L -rhamnose ( 46 ; Figure 15 ), D -mannose and abequose (3,6-dideoxy- D -xylo-hexose). The release of LPS on treatment with antibacterial agents plays a vitally important role in septic shock, which further leads to an inflammatory response likely resulting in death. Strategies for the control of LPS mediated pathophys-iological disorders are based on the inhibition of enzymes along the biosynthetic pathway thereof or the interference of cationic structures with the negative surface of lipid A [173] .

6.1 CMP–KDO synthase inhibition The enzyme 3-deoxy- D - manno -octulosonate cytidyltransferase (CMP–KDO synthase) is responsible for the activation of the KDO building block to be incorporated into the LPS layer. Consequently, this protein is a well-recognised target for antimicrobial agents. 2-Deoxy-KDO derivatives with dif-ferent amino moieties at position O-8 ( 47 ; Figure 16 ) were found to be good inhibitors against this enzyme [174] . Having the exposure of the patient to a multiagent treatment in mind, the synergistic effect of different classes of antibiotics were introduced as strategy. In this context, a derivative of KDO modified with an NH- L -ala- L -ala moiety at position

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AbeOAc

Man Rha Gal

Glc

Glc

GlcNAc

Gal Glc

Gal

Hep-OPO3

2-Hep

Hep

KDOKDO

O

n >10

O

OO

HN

O

PO- O

O-

O O

O

NHHO

POO

O

O

O

O

O

O

HO

OO

OH

OH

OO

O

43: LPS

OOH

COOH

OH

HO

HO

HO

O

OH

OHHO

OH

O OH

OH

OH

HO

HO

HO

44: KDO

46: Rha

45: Hep

Core

lipid A

O-antigen side chain

Figure 15. Structure of lipopolysaccharides (LPS; 43 – 46) .

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O

OH

HO

COOHHO

R

47: R = NHC(NH)NH2 R = N(CH2CH2COONH2)2 R = NHCO2CH2C6H4-OMe-4 R = NHCO2CH2C6H4-NO2-4

O

OH

HO

COOHHO

H2N

OHN

O

NH

48

O

O

NHO

HO

HO O

O

NH

OHO

O

O

O

HO

O

OH

HO

O

26

12

12

12

12

49

O

HO

OH

COONa

OH

OH

O

O

OH

HO

HOOR

COONa

50: R = (CH2)3OH R = CH2COONa R = (CH2)2COONa R = (CH2)3COONa R = (CH2)4COONa R = (CH2)2CH = CHCOONa R = (CH2)3SCH2COONa

Figure 16. Structures of O-8-substituted 2-deoxy-β-KDO analogues (47), 8-NH-L-ala-L-ala KDO analogue (48), C-3 fatty acid ether linked lipid (49) and modifi ed α-KDOp-(2,8)-α-KDOp derivatives (50).

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O

R2

R1

O

NH

O

OH

C13

H27

O

51: TU-514 R1 = OH, R2 = OH52: R1 = H, R2 = OH R1 = OH, R2 = H R1 = OH, R2 = OMe R1 = OMe, R2 = H

Figure 17. Structures of TU-514 (51) and modifi ed 2-hydroxamic acid N-acetyl-D-glucose derivatives (52).

C-8 ( 48 ; Figure 16 ) in combination with kanamycins was designed showing potent effects on inhibition of the production and/or release of Vero toxins produced by enterohaemorrhagic E. coli [175] . Recently, the potential of LPS from Rhizobium Sin-1 was investigated to develop therapeutics for the prevention or treatment of septic shock on the antagonistic properties. A derivative of the unusual R. Sin-1 lipid A was synthesised, in which the linkage of the fatty acid substituent at position C-3 was changed from an ester to an ether conjugation, allowing for better chemical stability ( 49 ; Figure 16 ) [176] .

The bacterial family Chlamydiaceae is composed of two genera with a total of four species, all of which are obligatory intracellular pathogens causing a broad variety of serious diseases in animals and humans. A library of monoclonal antibodies ( 50 ; Figure 16 ) against specific LPS structures in a mouse model recognised by KDO was generated to explore the molecular basis of antigen recognition processes and shed light on the inherent KDO binding pocket. This expla-nation is believed to be significantly helpful for the design of better tools for the clinical diagnosis of chlamydial diseases in humans [177,178] .

Although it was recognised that the KDO-subunit in the construction of LPSs is species-specific besides the overall well-conserved structure of LPS, the development of KDO analogues as potential inhibitors remains difficult and no inhibitor of any enzyme in the LPS biosynthetic pathway has been developed into a clinical drug thus far.

6.2 LpxC inhibition An attractive target in the LPS biosynthetic pathway is UDP-3- O -(R-3-hydroxymyristoyl)- N -acetylglucosamin deacetylase (LpxC), a zinc-dependent metalloamidase that catalyses the first committed step in the biosynthesis of lipid A, the hydrolysis of UDP-3- O -( R -3-hydroxymyristoyl)- N -

acetylglucosamine to acetate and D -glucosamine. For this enzyme no sequence homologies to any other enzymes including mammalian metalloamidases is known thus far [179,180] . By NMR, calculations of the density functional theory and X-ray crystal structure studies, hydroxamic acid moiety containing compounds were found to inhibit this protein by chelating the metal ion in the active site, thereby mimicking a pyrophosphate group [181-183] . On the basis of these findings, the rational design towards a more substrate-like structure led to the synthesis of related carbohydrate-containing structures. In this context, TU-514 ( 51 ; Figure 17 ), an N -acetyl- D -glucose residue that carries a hydroxamic acid at position C-2 and a lipid ester at position O-3, was synthesised. The remaining hydroxyl groups at the sugar allow for further modification ( 52 ; Figure 17 ). Such compounds are believed to serve as leads for the development of novel antibiotics against Gram-negative bacteria [184-187] .

6.3 Rhamnosidase pathway inhibition In the O-antigen biosynthesis pattern the L -rhamnose pathway has also been taken into advantage as potential therapeutic target for rational drug design as humans do not synthesise dTDP-rhamnose. Inhibition of the thymidine diphosphate-(dTDP)-rhamnose biosynthesis from dTDP-glucose, wherein four enzymes are involved, and the rhamnosyltransferase (RhamT), which conducts the incorporation of L -rhamnose into the mycobacterial cell wall by glycosylation of GlcNAc-diphosphoprenyl, have been addressed in this context [188-

190] . The iminosugar deoxyrhamnojirimycin ( 53 ; Figure 18 ) was found to inhibit mycobacterial RhamT by mimicking the dTDP-rhamnose donor substrate or the transition state [191] . Interestingly, β -alkyl as well as β -aryl pseudoano-meric substituted rhamnomimetics ( 54 ; Figure 18 ) also showed inhibition activity against this enzyme. The fact that the corresponding α -pseudoanomeric analogues do not interact with the same protein suggests that the β -rhamno iminosugars mimic the donor substrate dTDP- β - L -rhamnoside or the transition state, which also carries a group at the β face of the rhamnosyl unit [191] . Furthermore, 1,6-dideoxy- L -nojirimycin (2- epi -1-deoxy- L -rhamnojirimy-cin, 55 ; Figure 18 ) [192] and bicyclic representatives of iminosugars such as L -swainsonine and related 6- C -methyl- -L -swainsonine derivatives ( 56 ; Figure 18 ) [193] as well as (-)-hyacinthacines A 2 and ent -7-deoxyalexine ( 57 ; Figure 18 ) [194] were found to show excellent inhibitory activities against naringinase from Penicillium decumbens , an α - L -rhamnosyl processing enzyme, showing the potential of iminosugar analogues for their use as antibacterial agents. In the pyrrolidine series, 1,4-dideoxy-1,4-imino- L -mannitol ( 58 ; Figure 18 ) [195] and (2 S ,3 S ,4 R )-deacetyl anisomycin ( 59 ; Figure 18 ) [196] showed inhibitory activity against naringi-nase. Furthermore, seven-membered ring iminosugar deriv-atives such as tetrahydroxyazepanes with D - and L -ido configuration ( 60 ; Figure 18 ) inhibit naringinase but lack selectivity [197] .

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The genetics and biosynthesis of the lipopolysaccharide inner core oligosaccharide units are not explained in the finest details, yet. Further explanation of the biosynthetic pathway of LPS will provide a great potential for the discovery of new targets. For example, the second sugar in the core region of LPS, L - glycero - D - manno -heptose, is highly conserved and not found in mammalian cells. Consequently, ADP- L - glycero - D - manno -heptose-6-epimerase, an enzyme that catalyzes the interconversion of ADP- β - D - glycero - D - manno -heptose and ADP- β - L - glycero - D - manno -heptose, is an interesting target for the design of mechanism- and structure-based inhibitors [198] . Another strategy could be envisaged by adopting anti-endotoxin properties of non-carbohydrate antibiotics, such as cationic peptides defensins, magainins and cecropins, that interact with the negative charge of the phosphate substituents of lipid A, to carbohydrate structures. Thereby, new agents active in the LPS pathway may be envisaged.

7. Aminocoumarin antibiotics

Aminocoumarin antibiotics are a group of antibacterial agents produced by different Streptomyces strains, which are active against Gram-positive pathogens such as S. aureus and S. epi-dermidis . All structures of this family contain a 3-amino-4,7-dihydroxycoumarin moiety (ring B), which is attached by means of an amide linkage to structurally different acyl sub-stituents (ring A). In the case of novobiocin ( 61 ; Figure 19 ), clorobiocin ( 62 ; Figure 19 ) and coumermycin A 1 ( 63 ; Figure 19 ) ring B carries an O-linked substituted deoxysugar, L -noviose (ring C), which is esterified at position O-3 with a

carbamoyl group (novobiocin) or a 5-methylpyrrole-2-carboxyl moiety (clorobiocin). These antibacterial agents inhibit DNA gyrase, an enzyme essential for bacteria but not found in humans, by binding to the B subunit of the heterotetrameric enzyme. This binding site overlaps with the ATP-binding site located on GyrB. Consequently, aminocoumarines inhibit ATP hydrolysis required for ATP-dependent DNA supercoiling [199] . Additionally, these antibacterial agents inhibit DNA topoisomerase IV, which is a type II topoisomerase similar to gyrase and is involved both in the control of DNA supercoiling and in the decatenation of daughter chromosomes after DNA replication. The crystal structure of an E. coli gyrase B fragment and clorobiocin complex revealed that the novobiose sugar and the attached pyrrole ring superimpose with the adenine ring and ribose of ATP. Furthermore, the pyrrole moiety of clorobiocin is located in a hydrophobic pocket displacing two ordered water molecules resulting in a two- to sixfold increase in inhibitory activity compared to novobiocin [200] . The biosynthetic gene clusters of all three antibiotics have been sequenced and the functions of nearly all the genes have been explained [201] . Thus, combinatorial biosynthesis has become a versatile tool for the generation of new aminocoumarin antibiotics [202] . For example, the addition of synthetic analogues of the A ring to specific mutants of novobiocin and clorobiocin producers, an approach called mutasynthesis, generated a series of new structures. The screening determined against Staphylococcus and Streptococcus strains and other relevant pathogens identified highly active compounds and confirmed speculations that a non-polar side chain attached to the benzoyl moiety of novobiocin and

HN

OH

OHHO

53: Deoxyrhamnojirimycin R = H54 β-alkyl DRJR = (CH2)7CH3

HN

OH

OHHO

55: 2-epi-L-DRJ

R

N

HO

HOOH

R

56: SwainsonineR = H 6-C-methyl swainsonine or R = CH3

N

HOH

OH

OH

57: Hyacinthacine A17aS Hyacinthacine A2 7aR

NH

OH

CH2OH

HO OH

NH

O

HO OHMeO

58: L-DIM 59: Deacetyl anisomycin

HN

HO

OHHO

OH

60: D-ido tetrahydroxyazepane

7

Figure 18. Structures of L-deoxyrhamnojirimycin (53), β-alkyl DRJ (54), 2-epi-L-DRJ (55), swainsonine, 6-C-methyl swainsonine (56), hyacinthacine A1 and A2 (57), L-DIM (58), deacetyl anisomycin (59) and D-ido tetrahydroxyazepane (60).

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O

HN

61: Novobiocin R1 = C(O)NH2, R2 = CH3

62: Clorobiocin R1 =

R2 = Cl

O

NH

O OO

OHOH

R2

O

OH

OR1

OA

BC

L-noviose

O

NH

O OO

OH

Cl

O

OH

O

O

O

NH

NH

O

O

HN

OO

OH

Cl

O

HO

O

O

O

HN

63: Coumermycin A1

HO

HO

HO

O

HO

OH

OO

O

O

O

NH

O

O

OH

O

Cl

HO

O

O

D-olivose

64: Simocylinone D8

Figure 19. Structures of novobiocin (61), clorobiocin (62), coumermycin A1 (63) and simocyclinone D8 (64).

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clorobiocin may be important for the uptake into bacteria [203] .

Simocyclinone D8 ( 64 ; Figure 19 ), isolated from Streptomyces antibioticus Tü 6040, is structurally related to aminocoumarin antibiotics with a difference in the carbohydrate moiety. Instead of L -noviose at position O-7 of the aminocoumarin ring A, this compound carries a D -olivose residue that features a tetraene dicarboxylic acid attached to position O-3 as acyl moiety. Simocyclinone D8 behaves differently compared to aminocoumarines; it is a potent inhibitor of gyrase but do not inhibit the DNA-independent ATPase reaction of GyrB. Binding studies reveal interaction with the N-terminal domain of GyrA. Therefore, this agent inhibits an early step of the gyrase catalytic cycle by preventing binding of the enzyme to DNA [204] .

The diversity of new structures in the aminocoumarin family obtained by combinatorial biosynthesis will be expanded by

further genetic modifications of the gene deletion mutants, thereby offering a large pool for lead finding in this structure class of antibiotics.

8. Miscellaneous carbohydrate antibiotics

8.1 Arabinosyltransferase inhibitors β - D -Arabinosyltransferases are responsible for the assembling of the repeating lipopolysaccharide cell wall (lipoarabinomannan and lipoarabinogalactan), which is specific for MBT. These glycans are built from arabinofuranosyl units that are not found in mammals and, therefore, are appropriate targets for antibacterial agents. Mimetics of decaprenolphosphoarabinose (DPA), the donor substrate of arabinosyltranferases, a sugar nucleotide donor or oligosaccharide substrates are potential arabinosyltranferases inhibitors. In this context, C-phosphonate analogues of DPA ( 65 ; Figure 20 ) were designed and showed

OO

HO OH

(CH2)7CH3

O

HO OH

N

67: Dicyclohexyl glycosyltransferase substrate analogue

65: Phosphonate analogue of DPA

O

PO

O(CH2)15CH3

O

O-O

HO OH

HO

66: C45 prenylmimics of DPAX = O, N

O

7

O

P

O

O-

X

HO OH

HO

Figure 20. Structures of phosphonate analogue of DPA (65), C45 prenyl mimetic of DPA (66), dicyclohexyl glycosyltransferase substrate analogue (67), disubstituted analogues (68), arabinosyl hybrids (69) and (70) .

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Figure 20. Structures of phosphonate analogue of DPA (65), C45 prenyl mimetic of DPA (66), dicyclohexyl glycosyltransferase substrate analogue (67), disubstituted analogues (68), arabinosyl hybrids (69) and (70) (continued).

XO

HO OH

O

HO OH

N

N

68: Disubstituted analogues, X = O, C

N

HO

OH

R O(CH2)8COOMeO

HO OH

69: Arabinosyl hybrids, R = CH3, OH

N

HOX

HO OH

O(CH2

70: Arabinosyl hybrids, X = C, O

the ability to prevent growth of MBT [205] . Another DPA mimetic, featuring a C 45 prenyl moiety attached to the arabinosylphosphonate as well as the respective iminosugar analogue ( 66 ; Figure 20 ), showed in preliminary biological evaluations encouraging activities against MBT by specific inhibition of arabinosyltranferase in the same concentration as ethambutol [206] .

Knowing that glycosyltranferases tolerate modifications in the catalytic pocket, a disaccharide substrate analogue carrying a large sterically basic dicyclohexylamino substituent at posi-tion 5' ( 67 ; Figure 20 ) was designed. This compound turned out to be active in an in vitro assay against MTB [207] . Disubstitution at positions 1 and 5' with different types of the linkage between the units, such as in analogue 68 ( Figure 20 ), also showed activity against MTB [208] .

Iminosugar–arabinofuranoside hybrids such as compound 69 ( Figure 20 ) showed interesting arabinosyltransferase inhibitory properties. The length of the attached arabinofuranoside moiety was found to modulate the activity of such compounds [209] . In this context, a next generation of structures were synthesised by either replacing the hydrolytically labile O-glycoside by a C-linkage or by introducing a carbasugar mimetic of the arabinofuranoside moiety as shown in hybrid 70 ( Figure 20 ). The C-glycosyl analogue showed the same level of microbicidal activity than the O-glycoside [210] .

8.2 Monosaccharide antibiotics Three new C1-alkylated six-membered iminosugars, batzellasides A, B and C ( 71 ; Figure 21 ), were isolated from Batzella sp., and found to inhibit the growth of S. epidermidis [211] .

Galactosylglycerols ( 72 ; Figure 21 ), isolated from the red alga Chondria armata (Kütz.), were found to show antimicrobial activity against several pathogens such as the bacteria Klebsiella sp. and Shigella flexneri [212] .

Two novel antibiotics, neocitreamicin I and II ( 73 ; Figure 21 ), were recently isolated from the fermentation broth of a Nocardia strain (G0655) and found to belong to the citreamicin group, which are members of the polycyclic xanthones. Both structures showed in vitro activity against Gram-positive bacteria including strains of MRSA and VRE [213] .

The genome analysis of secondary metabolite biosynthesis of the vancomycin producer Amycolatopsis orientalis ATCC 43491 revealed the presence of genetic loci for the production of at least ten structures. One of the gene clusters containing a type I polyketide synthase was found to synthesise a glyco-sidic polyketide named ECO - 0501 ( 74 ; Figure 21 ), which showed strong antibacterial activity against a series of Gram-positive pathogens including strains of MRSA and VRE. Preliminary explanation of the mode of action suggested a potentially novel cell membrane and/or cell wall target specific to bacteria [214] .

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HN

HO

HOOH

n

71: Batzellasides n = 7,8,9

(CH2)14CH3

O

O

O

O

HO

OH

OH

OHO

OR

72: Galactosylglycerols HR, =

O

NO

O

O

O

OHO O

O

O

O

OOAc

OH

73: Neocitreamicin II

HN

N NH2

NH

OO

OH

O

O

OH

HOOC

HO OH

74: ECO-0501

OH

Figure 21. Structures of batzellasides (71), galactosylglycerols (72), neocitreamicin II (73) and ECO-0501 (74).

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In the lincosamide family, which contains an amino sugar moiety conjugated to an amino acid residue, clindamycin ( 75 ; Figure 22 ) is the most widely used antibiotic offering an effective therapeutic alternative to β -lactam antibiotic treatment for MRSA strains. Recently, by changing the ring size of the pyrrolidine residue, an azetidine lincosamide library ( 76 ; Figure 22 ) was done and several compounds thereof showed a similar antibacterial spectrum of in vitro potency to that of clindamycin [215] .

Lauric acid, a twelve carbon chain fatty acid is known to be active against both Gram-positive as well as Gram-negative bacteria. In this context, synthetic methyl-6- O -lauroyl- β - D -glucoside and the corresponding α - D -mannoside ( 77 ; Figure 22 ) showed even better activity against the Gram-positive S. aureus , supporting the hypothesis that the carbohydrate moiety is essentially involved in the antimicrobial efficacy [216] .

In an effort to improve the therapeutic values of thiocarlide (THC), a non-carbohydrate-containing anti-tuberculosis therapeutic agent, several N -glycosyl- N ’-[ p -(isoamyloxy)phenyl]-thiourea derivatives were synthesised and biologically evaluated against MBT . The arabino analogue 78 ( Figure 22 ) was found to be more potent than THC itself whereas the D - ribo configuration displayed a MIC value in the same range as THC. The c LogP value of the glycosylated THC versions is 1.56 and is significantly lower than that of THC (6.22), which may result in an increase of bioavailability [217] .

8.3 Oligosaccharide antibiotics Oligosaccharide antibiotic agents consist of a complex carbohydrate core built up of various sugar units and an aglycon such as aromatic systems, lipid chains and other unpolar substituents. For example, the moenomycin family contains a core of at least three sugar units that may display chain branches and carry an O-glycosidic phospholipid substituent. These structures were found to show activity against Gram-positive bacteria by inhibiting the transglycosylation in the peptidoglycan biosynthetic pathway through binding directly to the trans-glycosylation domain of the enzyme, thus, preventing polymerisation of lipid II into linear peptidoglycan. For example, moenomycin A (flavomycin, 79 ; Figure 23 ) [218] and related structures were found to first bind to the cytoplasmic membrane through the lipid moiety followed by a highly selective interaction of the trisaccharide unit to the donor binding site of the respective enzyme [219] . These findings have prompted scientists to synthesise smaller derivatives thereof in an attempt to cut down the molecular size and to develop improved antibiotics. However, owing to poor bioavailability, this agent is now used as a growth promoter in animal feed. Domain requirement studies and development of high through-put screening methods as well as combinatorial synthesis for the construction of diversified moenomycin A structures may facilitate the identification of new transglycosylase inhibitors [220,221] .

Hexasaccharide 80 ( Figure 23 ) was found in a glycoprotein secreted from deeper mucins and discovered to inhibit

O S

OH

OH

HO

NH

ClO

N

75: Clindamycin

O

OH

R1

R4

R3

R2

HO

O

O

77: Lauroyl-β-D-glucoside I: R1 = OCH3, R2 = H, R3 = OH, R4 = H; Lauroyl-β-D-mannoside II: R1 = H, R2 = OCH3, R3 = H, R4 = OH;

O S

OH

OH

HO

NH

ClO

N

R′

R

76: Azetidine lincosamide R = alkyl

O

HO

HO OH

NH

NH

SO

78: THC arabino analogue

9

Figure 22. Structures of clindamycin (75), azetidine lincosamides (76), b-D-gluco and a-D-manno lauroyl glucosides (77) and THC D-arabino analogue (78).

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O

OHO

O

O

O

NH2

P OO

O

H2N

O

O

O

OH

NHAc

O

O

OHHO

HO

OH

O

HO

HN O

O

OHN

HO

HO

OH

OHO

79: Moenomycin A

OH

COOH

O

O OMe

NHAc

O

HO

O

O

OH

OH

O

OH

O

HO

HO

HO

NHAc

O

HO

O

NHAc

O

OH

OH

O

OH

O

HO

HO

HO

NHAc

80: Hexasaccharide against H. pylori

Figure 23. Structures of moenomycin A (79) and hexasaccharide against Helicobacter pylori (80).

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Helicobacter pylori growth. The first total synthesis of this complex carbohydrate structure was achieved and the developed facile methodology will be helpful for structure–activity relationship studies in this context [222] .

Orthosomycins are antibiotics produced by several Streptomyces species, various members of this family are active against Gram-positive pathogenic bacteria including resistant strains such as glycopeptide-resistant Enterococci , MRSA and penicillin-resistant Streptococci [223] . Examples of this family are avilamycins, everninomicins and gavibamycins, which consist of a complex structure: a heptasaccharide chain including one or more interglycosidic spiro-ortholactone linkages is conjugated to a polyketide-derived dichloroisoeverninic acid moiety. Avilamycin ( 81 ; Figure 24 ) and evernimicin (Ziracin [Schering-Plough, Kenilworth, NJ, USA], 82 ; Figure 24 ) were shown to inhibit protein biosynthesis by binding to the 50S ribosomal subunit of the bacterial ribo-somes interacting with the ribosomal A-site and interfering with initiation factor IF2 and tRNA binding [224] . However, Ziracin already passed through Phases II and III of clinical studies but further development as a drug was stopped owing to a mismatch of activity to side effects. Molecular cloning and characterisation of the genes governing their bio-synthesis might set the direction for the development of new antimicrobial agents [225] .

8.4 Carbohydrate-containing nanoparticles and dendrimers Recent advances have accelerated the design of novel structures allowing for the finding of potential drug candidates. Hand in hand there has also been a renewed effort aimed at strategies for advanced drug protection and delivery. In this context, nanoparticles are thought to improve the bioavailability and efficacy of pharmaceutical compounds attached to them. Glycosylated polyacrylate nanoparticles that contain a variety of protected and unprotected monosaccharides within the polymeric framework in combination with antibiotic agents such as certain β -lactams or ciprofloxacin covalently bound on the outer sphere, so called glyconanobiotics, have been synthesised and biologically evaluated. For example, compound 83 ( Figure 25 ) showed powerful in vitro activities against S. aureus , MRSA as well as Bacillus anthracis [226] .

Glycodendrimers and glycopolymers that mimic the carbohydrate glycocalix of cells, which plays a crucial role in bacterial adhesion, often a prelude to infections, are believed to be helpful for the intervention of this early event by inhibition of the initial recognition leading to adhesion and colonization of host tissue [227] . Glycodendrimers were synthesised using a structure-based design at the monovalent level and are believed to demonstrate highly attractive alternatives to conventional antibiotics [228,229] . For example, the multivalent highly flexible glycodendron 84 ( Figure 25 ) showed inhibition of the adhesion of type 1 fimbriated E. coli to mannan in an ELISA [230] . The tetravalent galabiose disaccharide 85 ( Figure 25 ) showed inhibition capacities against Streptococcus suis

D 282 with a MIC in the nanomolar range [231] . The anti-adhesion strategy with multivalent glycodendrimers is considered an alternative intervention method against microbial pathogens compared to the targets of the classical antibiotic agents.

9. Conclusion

The synthesis of novel chemotherapeutic agents as well as detection of new targets and development of new strategies in bacterial therapy still remains very complex and time as well as budget consuming. However, scientists as well as com-mercial producers are aware of the pervasive and increasing threat of bacterial diseases by resistant strains. There is the urgent need for new antibiotic agents. Although the number of non-sugar-containing antimicrobial agents by far exceeds carbohydrate-containing antibiotics, their increasing impor-tance cannot be dismissed. With the growing understanding and appreciation of the role of the carbohydrate part in antibacterial agents, carbohydrate-manipulating enzymes in the biosynthetic machinery of bacteria and the acquisition of importance of carbohydrate-related interactions in micro-organisms, the role of the sugar components is better under-stood. In glycopeptide antibiotics the sugar moieties are responsible for the formation of the biologically active con-formation of the peptide backbone to be able to interact with the target. In aminoglycosides the sugar structures with the 1,2- and 1,3-aminol units are responsible for providing protons in a preorganised spatial arrangement for H-bonding with the target. In macrolide antibiotics, however, the role of the carbohydrate residues remains unclear, the explana-tion bears an immense potential for further work in this field. Nucleoside antibiotics are very often substrate ana-logues for the respective enzymes. The nature of the nucleo-side moiety is intrinsically necessary for the interaction with the target. The same is true for inhibitors of KDO synthase and rhamnosidase, two enzymes along the Lpx biosynthetic pathway. In aminocoumarin antibiotics the sugar moiety seems to be important for the binding to gyrase because it is found to superimpose with the ribose moiety of ATP in the complex with the same enzyme. In general, it is well-known that the presence of hydrophilic sugar residues has a positive influence on antibacterial drugs such as better bioavailabil-ity, stability and adsorption characteristics. The large reper-toire of targets and the diverse responsibilities in mechanisms of action addressable with the sugar parts of carbohydrate-containing antibacterial agents allows for many different starting points of creative design of novel structures and development of new strategies in antibiotic research. Several carbohydrate-containing antibacterial agents are in clinical phase trials, for example, oritavancin, telavancin or ramoplanins in the family of glycopeptides antibiotics as well as tiacumicin B, cethromycin or EDP-420 in the class of macrolide antibiotics. Great efforts can be seen in the development of new, most frequently semisynthetic structures in the class of aminoglycoside

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81:

Avi

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, R1

= H

, R2

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, R3

= C

(O)C

H3,

R4

= C

H3

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O

O

O

O

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O

O

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O

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R3

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82).

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O

O

O

O

O

O

O

O

O

O

O

OO

O

O

N

N

O

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OH

N

N

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N

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N

O

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N

N

O

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O

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HO

N

N

O

N

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F

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83: Glyconanobiotic

Figure 25. Structures of glyconanobiotic (83), glycodendron (84) and tetravalent galabiose disaccharide (85).

and nucleoside antibiotics having potential as antimicrobial drug candidates. Rational design for the development of compounds that target different enzymes along the biosynthesis of membrane-bound lipopolysaccharides is seriously and successfully done. Iminosugars as transition state ana-logues of bacteria specific enzyme substrates and other monosaccaridic structures that are conjugated to lipophilic moieties including lincomycin derivatives promise to have

the potential for lead structures. Additionally, complex oligosaccharides such as found in the moenomycin and orthosomycin family as well as novel composites such as carbohydrate nanoparticles, glycodendrimeres and glycopolymers with interesting antibacterial properties complete the structural diversity available at present. Unfortunately, drawbacks such as in the case of Ziracin, a complex oli-gosaccharide antibiotic (everninomicin) that was discontinued

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because of unsatisfactory results from completed Phase II and Phase III in 2000, depict how close success and failure lie together, displaying the financial threat of antibiotic research for companies.

10. Expert opinion

Contrasting the assumption made only a few decades ago, that most of the bacterial diseases can be treated successfully and that this health care problem is practically solved, nature taught us better. The appearance of (multi)resistance and ‘superbugs’ over the past 30 years is a recognised threat and meanwhile is dramatically increasing worldwide [232] . Scientists, companies and government authorities are in agreement that there is des-perate need for the development of novel antimicrobial agents to tackle this problem. This goal is thought to be reached by the development of agents with improved antibacterial activities addressing known as well as new targets [3] . In this context, efforts have been visible over recent years, but it seems, not to the extent needed. Today only 1.5% of all drugs developed by the pharmaceutical industry are antibiotics. The most common methods for the development of novel structures are rational drug design and chemical and/or enzymatic modification

based on known antibacterial agents to gain advanced chemotherapeutic properties such as broad-spectrum antimi-crobial activity, the ability to overcome multidrug resistance as well as better stability. The screening of microorganisms for new antibacterial agents and the explanation of new targets for antibiotics are common strategies. Additionally, the rapid development of computational sciences, such as molecular modelling of the agent–target complex, databases and screening of virtual libraries for lead finding in combination with analytical methods including advanced NMR technologies and X-ray crystallography became important supportive tools for this effort. Novel techniques for the explanation of biosynthetic pathways help to gain better insight into nature’s secrets and lead to a growing understanding of the genomics of microorganisms. This will further accelerate the progress of designing potential antibacterial agents. In this context, methods such as recombinant approaches for manipulating the production line of microorganisms as well as combinatorial biosynthesis, which use biosynthetic genes as tools to develop new drugs, will help to identify novel structures. This concept was applied to enzymes of sugar bio-synthesis to manipulate the glycosylation patterns allowing for the biosynthesis of natural products with the possibility of a

Figure 25. Structures of glyconanobiotic (83), glycodendron (84) and tetravalent galabiose disaccharide (85) (continued).

O

O

HO

O OH

OMe

O

O

O

HO

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HO

HO

OH

HO

HO

HO

HO

84: Glycodendron

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COOMe

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O

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O

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HO

HO

HO

O OO

O

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OH

OH

OH

HO

HO

HO

85: Tetravalent galabiose

Figure 25. Structures of glyconanobiotic (83), glycodendron (84) and tetravalent galabiose disaccharide (85) (continued).

great glycodiversification [233] . The investigation of mirror images of known structures such as D -peptides, L -RNA/DNA as well as L -sugars provides another interesting approach for development of antibiotics [234] . The decoration of non-carbohydrate-containing antibacterial agents with sugar residues can influence the drug profile in terms of better adsorption, distribution, metabolism and elimina-tion characteristics in a positive sense. The use of the syner-gistic effects of novel data-driven computational tool kits with reliable synthetic methods and combinatorial synthesis as well as modern high throughput screening methods and SAR studies are of great benefit to this research field.

Authorities are addressed urgently to develop strategies for the appropriate use of antimicrobial agents to maximise their therapeutic impact and to minimise the development of resis-tant strains.

The screening of every individual case allowing for an optimal specific case dependent antibacterial treatment is an idealised scenario but a possible strategy to overcome the rapid devel-opment of resistance against new entrees of antibacterial agents soon after their launch.

The widths of the chemical space still bear a huge unexplored area and the combined achievements of chemists, biologists and clinicians should support the success in generating strategies for the development of novel carbohydrate containing antibacterial agents.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Affi liation Georg Schitter & Tanja M Wrodnigg † † Author for correspondence Technical University Graz, Institute of Organic Chemistry, Univ.-Doz. TMW, Dip.-Ing. GS, Glycogroup, A-8010 Graz, Austria Tel: +43 316 873 8744 ; Fax: +43 316 873 8740 ; E-mail: [email protected]

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Update on carbohydrate-containing antibacterial agents