Dr. Bilal Aljaidi. Antibacterial agents: Antibiotic: any substance produced by a microorganism that...
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Medicinal Chemistry-2 Dr. Bilal Aljaidi
Dr. Bilal Aljaidi. Antibacterial agents: Antibiotic: any substance produced by a microorganism that is antagonistic to the growth of other microorganisms
Antibacterial agents: Antibiotic: any substance produced by a
microorganism that is antagonistic to the growth of other
microorganisms (mainly bacteria) in high dilution (Waksman 1942).
Antimicrobial agent: is a substance that kills or inhibits the
growth of microorganisms such as bacteria, fungi, or protozoans.
Either kills the microbe (microbiocidal) or prevent its growth
(microbiostatic). covers both antibiotics and synthetic agents
Slide 3
Antibacterial agents: Infection is the colonization of the host
organism with a microorganism like bacteria, parasite, virus, or
even a macro organism like fungi and macro parasites such as worms
and nematodes. The microorganism then will use the host resources
to reproduce and grow that results in a disease. Host system
normally use the immune system to fight against the invading
organism, first by the innate immune system, then by the adaptive
immune system.
Slide 4
History of Antibacterial agents: The presence of bacteria was
first identified in 167o by Van leeuwenhoek. Pasteur was the first
who link the bacteria to disease in 1800. Lister introduced
carbolic acid as antiseptic and sterilizing agent for the operating
wards. Koch identified that some bacteria is responsible for
specific infections such as tuberculosis, cholera and typhoid
Slide 5
History of Antibacterial agents: Paul Ehrlich the father of
chemotherapy developed the principle of chemotherapy: a chemical
could directly interfere with the proliferation of microorganism at
a concentration tolerated by the host.. This was named the magic
pullet.. Which is nowadays called the selective toxicity. In 1910,
Ehrlich had developed the first synthetic antibacterial agent;
Salvarsan, which is active against protozoa especially
trypanosoma.
Slide 6
History of Antibacterial agents: In 1934, Proflavine was used
in the wound infections, due to its systemic toxicity, it did not
used systemically. In 1935, Prontosil was discovered as effective
antibacterial agent in vivo. later found to be a prodrug that
release sulfanilamide as the active metabolite:
Slide 7
History of Antibacterial agents: Sulfonamides were the only
effective antibacterial agents until the discovery of Penicillins
in 1940. Streptomycin was discovered in 1945 and used against
tuberculosis and other gram ve bacteria, then lead to the discovery
of other aminoglycosides. Streptomycin
Slide 8
History of Antibacterial agents: Chloramphenicol and
tetracycline antibiotics were discovered in 1947. In 1955,
Cephalosporins were discovered. Many synthetic antibacterial agents
were prepared later such as quinolones (1962), Flourinated
quinolones (1980),Linezolid (2000) and other sulfonamide
derivatives with a broad spectrum activity.
Slide 9
The extensive studies on the bacterial cell components, genome
and metabolic pathways considerably helped in better understanding
the essential metabolic stages that are important for the growth
and proliferation of the bacterial cells, which means that
targeting these pathways might result in killing or attenuating the
bacterial growth. Also the absence of certain essential bacterial
metabolic pathways means that targeting such reaction could result
in selective bacterial killing without harming human cells and
result in safe antibacterial agents
Slide 10
Bacterial cell Is a prokaryotic cell. Differ significantly from
eukaryotic cells: 1-10 m length whereas eukaryotic length is 10-100
m Has no nucleus. Circular DNA, no chromosomal structure. Most of
the organelles are simpler that eukaryotics. Characteristic cell
wall which differ from bacteria to another, but generally, it is
thick and fatty envelope which protect the bacterial cell from
lysis and invading by external environment.
Antibacterial agents acting on the cell wall biosynthesis
Penicillins and Cephalosporins
Slide 15
-lactam antibiotics Cephalosporin nucleus Penicillin nucleus
Monobactam nucleusCarbapenem nucleus BA DC 5-membered thiazolidine
ring Carbon atom monocyclic 6-membered dihydrothiazine
Slide 16
Penicillins
Slide 17
Highly strained structure due to the presence of bicyclic fused
system composed from four membered lactam ring fused to the five
membered thiazolidine ring. Bacteria synthesizes penicillin using
cysteine, valine and some of the fermentation products:
Slide 18
Penicillins Difficult to synthesize in the lab due to: The
unstable highly strained ring system. The three chiral centre it
has which should be with certain stereochemistry. Beechams was
successfully isolated the biosynthetic precursor; 6-APA that was
used as an intermediate for the synthesis of most of the
semisynthetic penicllins.
Slide 19
The bacterial cell wall Peptidoglycan = a vital component of
bacterial cell walls, responsible for its shape and integrity
Peptidoglycan = macromolecule made of sugar (glycan) chains
cross-linked by short peptide bridges The nature of the peptidic
cross links varies among bacteria but the essential mechanism is
similar
Slide 20
The bacterial cell wall Gram + Consists of 50-200 peptidoglycan
layers Gram Only two layers of peptidoglycan Peptidoglycan
N-acetylmuramic acid (NAM) N-acetylglucosamine (NAG) D-alanine
Transpeptidase Involved in cross- linking
Slide 21
D-ala D-ala (natural substrate) Penicillins Penicillin-enzyme
complex cross-linking inhibited The wall become fragile and can no
longer prevent the cell from swelling and bursting Bacterial cell
lysis Excellent selective toxicity +
Slide 22
Penicillin mimic the structure of D-ala-D-ala, because of that
the transpeptidase mistakenly bind to it instead of D-ala-D-ala.
Also this explains the lack of penicillin toxicity, since D-amido
acids are not present in human, only the L- amino acids present.
Also targeting the cross linking in the peptidoglycan biosynthesis
which is only present in bacteria explains the selective
toxicity.
Slide 23
Structure-activity relationships of penicillins (SAR) The
strained -lactam ring is essential. The free carboxylic acid is
essential (the carboxylate ion binds to the charged nitrogen of the
lysine at the active site. The bicyclic system is essential. The
acylamino side chain is essential. Sulfur is not essential. The
stereochemistry of the bicyclic ring with respect to the acylamino
side chain is important.
Slide 24
Structure-activity relationships of penicillins
Slide 25
Acid sensitivity of penicillins
Slide 26
Three reasons for the acid sensitivity of penicillin G: Ring
strain: due to the large angle and torsional strain exist, acid
catalyzed ring opening will relief these strains. A highly reactive
-lactam carbonyl group: This amide bond is exceptionally unstable
compared to the normal amide (why?).. The stabilization of the
amide bond by the resonance is impaired here due to the increase in
the ring strain that will be formed after the delocalization of the
nitrogen lone pair to form a double bond within the four memeberd
lactam ring
Slide 27
Acid sensitivity of penicillins The effect of the acyl side
chain: It has a self-destructive mechanism in which the oxygen of
the carbonyl group will attack the carbonyl carbon of the lactam
ring causing the ring opining just like the attack of water
previously mentioned. This gives Penillic acid and penicillenic
acid as final products (explain the mechanism of formation?)
Slide 28
Slide 29
Acid resistant Penicillins To reduce the acid instability of
penicillins: We can not change the -lactam. We can not change the
bicyclic system and its ring strain. The only thing that can be
modified is the acyl group in order to reduce the self destructive
mechanism (How?). This can be done by decreasing the
nucleophilicity of the carbonyl oxygen which can be done by adding
electron withdrawing group.
Slide 30
Acid resistant Penicillins
Slide 31
-lactamase (Penicillinase): The wide spread use of penicillin G
led to the increase in the number of resistant strains, especially
in S. aureus. The main mechanism of resistance is the production
and secretion of -lactamase enzyme. -lactamase is a mutated version
of transpeptidase which is closely related in structure, especially
in the active site. This means that -lactamase will interact with
penicillin structure in the same manner as transpeptidase.
-lactamase can hydrolyze 1000 penicillin molecule per second
because the cleaved penicillin will leave the active site to react
with other molecule.
Slide 32
-lactamase (Penicillinase): Gram +ve bacteria normally release
-lactamase to outside of the cell that will cleave penicillin
before reaching the bacteria. Gram ve bacteria release -lactamase
into the periplasmic space, which again will cleave penicillin
before reaching the plasma membrane. Penicillin has to reach the
plasma membrane where the transpeptidase present to do its
antibacterial action. 95% of S.aureus became resistant to
penicillins Most of gram ve bacteria are -lactamase producing
bacteria
Slide 33
-lactamase (Penicillinase): There are various types of
-lactamase enzymes: Some are selective against penicillins
(penicillinase). Some are selective against cephalosporins
(cephalosporinase). Some are non-selective, acting on penicillins
and cephalosporins at the same time.
Slide 34
-lactamase resistant Penicillins Structural modification has to
be made to penicillin structure to prevent the binding to
-lactamase active site. This was a difficult task since -lactamase
and transpeptidase have a very similar active site. The only
successful modification was by adding bulky group at the acyl side
chain (Steric Shield), but not too bulky because this proved to
reduce penicillin activity.
Slide 35
-lactamase resistant Penicillins 95% of S.aureus in hospitals
became resistant to methicllin (MRSA) which in turns are resistant
to most of the older generation penicillins
Slide 36
Isoxazoyl Penicillins Effective against -lactamase producing
strains. Acid stable due to the electron withdrawing effect of the
isoxazole ring. Used against S.aureus resistant bacteria.
Slide 37
Broad Spectrum Penicillins Factors affecting the extent of
penicillin activity: Chemical structure. The ability to cross the
cell wall. Their susceptibility to -lactamase. Their affinity to
transpeptidase enzymes.
Slide 38
Broad Spectrum Penicillins Chemical modification to get broad
spectrum penicillins: 1. Addition of hydrophobic group at the acyl
side chain found to improve activity against gram +ve but reduce it
against gram ve bacteria. 2. The addition of hydrophilic group at
the acyl side chain causes a reduction in activity.
Slide 39
Broad Spectrum Penicillins 3. Activity on gram ve enhanced when
a hydrophilic group was added at the -carbon in the acyl side
chain, such in ampicillin and amoxicillin. This polar groups help
the penicillin to pass through the porines that exist in the cell
envelope of the gram ve bacteria
Slide 40
Ampicillin and amoxicillin Broad spectrum penicillins. Acid
resistant penicillins (why?). Sensitive to -lactamase (why?).
Poorly absorbed through the mucus memebrane, this is due to the
fact that they formed a zwitter ionic molecule at physiological pH
(they contain a carboxylic acid and an amino group in their
structure. The oral bioavailability can be improved by masking one
of them, mainly the carboxylic acid. By preparing a prodrug
esters.
Slide 41
Ampicillin prodrugs The methyl ester did not give the same
improvement in absorption and activity (why?).
Slide 42
Ureidopenicillins They all have a urea group at the -carbon in
the acyl side chain. They have better activity compared to
amoxicillin and they are more resistant to -lactamase. Used
parenterally for gram ve infections especially P.aeruginosa. the
ureido group though to mimic Some of the peptidoglycan structure,
which means that it can bind to penicillin-binding protein
Slide 43
Carboxypenicillins They have a carboxylic acid at the -carbon
of the acyl side chain. They have broad spectrum activity.