ANTI-BACTERIAL Compounds

Germicide / antiseptic on skin & disinfectant on things

External use – most are oxidants:

Cl2, O3, I2, NaOCl, H2O2, KMnO4, Chloramine-T

Chloramine-T Phenol(s) Triclosan Methyl salicylate

Phenols: generally toxic through skin but <1.5 % is tolerable

egs. Lysol (= p-cresol), TCP (= trichlorophenol), phenol (carbolic acid, R=H), TriclosanListerine contains menthol, thymol, methyl salicylate and eucalyptol

CH3 SO2 NCl

NaHO R O

OH

Cl

Cl

Cl

OHCOOMe

Quaternary Ammonium Compounds - Mouthwash - R4N+ X-

N (CH2)15CH3

+Br -

OCH2CH2N

CH3

(CH2)11CH3

CH3

+Br

-

Cetyl pyridinium bromide Domiphen bromide(Life, Safeway brands, etc.)

Cetrimonium bromideis (CH3)3N+(CH2)15CH3 Br-

= cetrimide

NH

NH

NH

NH(CH2)6

NH

NH

NH

NH

NH NH

ClCl

Chlorhexidine –for gingivitis

INTERNAL USE:

Bacteria divided into Gram +ve and Gram -ve groups:

Crystal violet stain turns both purple but only Gram +ve reamin so after I2 treatment and an acetone-alcohol-water wash

Gram +ve have thick walls with no outer membrane and trap stainegs. Streptococcus, Staphylococcus, Pneumonococcus

Game –ve have thin walls with inner and outer membranes and do NOT retain the stainegs. Meningitis, Salmonella, E. Coli, Pseudomonas

TB (tuberculosis, consumption)(Mycobacterium tuberculosis) destroys lung tissue, still kills ca. 1-2M / y

WHO estimates 1/3 pop of earth carries TB bacteriumTB vaccine essentially wiped out TB in the West but ca. 424K/y drug resistant cases (ca. 30K/y are VERY drug resistant)

UVic case February 2009

rifampicin and isoniazid are most common treatment but procedure is long and many cut it short: as a result 1.2% of cases are resistant

Serious concerns that TB could reappear in West:

No new drugs for 40 years but ~ 30 now under study

A new Johnson &Johnson drug (R207910)is under trials that inhibits ATP synthase

Bayer is in trials with moxifloxacin

Novartis is in trials with a nitroimidazole

N

OH N

O

Br

R207910

THE SULFA DRUGS: effective against most Gram +ve, some Gram –ve

FOLIC ACID PABA p-aminobenzoic acid

N

N

N

N

NH

H2N

OH

CONH CHCH2CH2COOH

COOH

H2N COOH

We eat folic acid; bacteria make it from PABA: we can fool them using sulfanilamide so they die of vitamin deficiency

H2N SO2NHRN

N

N S

NR =

a sulfanilamide Sulfapyridine Sulfadiazine Sulfathiazole

H2N SO2NHO

N

sulfamethoxazole common in Canada

PENICILLINS (Narrow spectrum antibiotics)

History: Original mould: penicillin notatum (pencil shapes) discovered by Fleming while working on staph bacteria, left cover plate off and noticed bacteria did not grow near mould

Flory (Oxford, 1940) found way to extract penicillin out of mould, tried it on London policeman with blood poisoning from shaving cut.

Wartime: needed to make much more, (used bed pans in Oxford to grow mould) so in June 1941 took production to USA (15,000 gallon vessels)

Mould now: penicillin chrysogenumfound on a cantaloupe in Peoria, Illinois in 1943 gave better yields and is used to make Pen-G

N

S

O

RCONH

COOH

Pen-G has R- = CH2 Pen

OCH2-Pen H2N PenO N

Pen

CH3Cl

H2N Pen

OH

Penicillins: general formula includes the -lactam ring

Pen-V Ampicillin Amoxicillin Cloxacillin

You can make those other than Pen-G by feeding the mould the appropriate acid, RCOOH

Pen-G

Pen-G has to be injected: 600-2400 mg/day IV in 3-4 dosesUseful against most GRAM +ve plus pneumonia, meningitis,gonorrhea, gangrene, bone infections

Others can be taken orally:

Pen-V: 300mg per 8h, first oral one

Amoxicillin: most common, 250-500 mg per 8h

Ampicillin: best for urinary tract

Cloxacillin: approved for some resistant bacteria

Many people are allergic to Penicillins (especially G) – can lead to death!

HOW PENICILLINS WORK:

-lactam ring binds to a transpeptidase enzyme responsible for forming the cross links in the peptidoglycan layer (bacterial cell walls):

as the cell grows it needs to constantly break these layers: If it can’t expand, the cell bursts and dies

BUT some bacteria have Penicillinase, an enzyme that cleaves the -lactam ring and allows normal wall formation: resistant

PenOEt

R=

nafcillin

MeO OMePen

methicillin

Five Penicillins are more resistant to Penicillinase: mainly reserved for Staph infections (egs. Nafcillin and Methicillin)

CEPHALOSPORINS: from mould found in sewage (Sardinia 1950’s)

H2N Ceph

N

S

Z

COOHO

R-CONH

Z=Cl

NCeph

+

N

SH2N

CephN

OCH3

Z =

R = R =

internal -COO-

a cephalosporin Cefachlor (Ceclor) Cefepime (Maxipime)

250 mg/8h, 2g/day max 1 g/12h for 10 days

Very popular (~2B$/y)more effective than penicillins against Gram -ve types

CPS lists 16 in use all start with Cef-

Not affected by penicillinase but a cephalosporinase has now emerged

WIDE SPECTRUM ANTIBIOTICS: MYCINS and TETRACYCLINES

Streptomycin (from soil) in 1947 – stops cell division, shuts down protein/RNA synthesisToo toxic for use, then last resort for TB

Also from soil: the tetracyclines:

OH O OH O

CONH2

OH

N(CH3)2ZOHX

OH

Chlorotetracycline (Aureomycin)X=Cl, Z=OH

tetra-cyclo = 4 rings Tetracycline (Terramycin, (A,B,C,D) Ambramycin,.....)

X=H, Z=OH

More common ones now:OH O OH O

CONH2

OH

N(CH3)2ZOHX

OH

Doxycycline (Vibramycin) X=H, Z=OH, no OH in ring BMinocycline (Klinomycin) X=NMe2, Z=H, no OH or Me in ring BDemeclocycline (Declomycin) X=Cl, Z=H, no Me in ring B

Doses: 250-600 mg/6h

They inhibit protein synthesis by binding to the ribosome,

Kill most bacteria = broad spectrum including intestinal bacteria, so side effect is DIARRHEA

Eat pro-biotic yogurt when on this (and shortly after stopping)!!

Was used against Legionnaire’s Disease (Chicago 1976)

Ca salts, antacids bind to them: avoid milk and antacids

Side effects: browning of teeth (acne treatment for teens)photosensitive skinreduced effectiveness of birth control pills

Mostly excreted unchanged – high levels can be found in sewage!

Aside on Legionnaire’s disease: hundreds staying at one hotel fell ill (34 died) during the 1976 American Legion Convention in Chicago - discovered that the pneumonia-like illness was caused by a previously unknown bacterium, now known as Legionella pneumophillia. Turns out the bacteria proliferates in warm, stagnant water, in this case in the hotel air conditioning system. Subsequent outbreaks have occurred in 1999 (Netherlands flower show, 34 died), 2001 (Spain, hospital cooling tower, 6 died) and 2002 (UK, Art Center cooling tower, 7 died)

AMINOSUGARS (AMINOGLYCOSIDES)

ERYTHROMYCIN CLINDAMYCIN (Dalacin)

HOOH

O

O

O

O

OOH

OMe

OHO NMe2

N NH

HO

Cl

OH

OH

SMe

O

Very widely used More toxic allergic reactions rare usually only for more

serious infections

cross placenta and go in to breast milk

Dose: ~ 1 g/day in 2-4 doses; up to ~4 g/day in more serious cases

VANCOMYCIN

Last resort for many staph types:

interferes with wall synthesis

VRE = Vancomycin resistant enterococci (opportunistic gut infection) - in Canadian hospitals (see chart at right)

DAPTOMYCIN

NHNH

O

O

NH

NH

O

O

O

O

NH2

O

NHHOOC

NH

HOOC

NHO

O

HN

HN

O

NHO

O

HOOC

NH

H2NO

O

NH

O

NH

HN

(CH2)8CH3

NH2

HOOC

HO

used against VRE and methicillin resistant staph (MRSA)*

(stops synthesis of cell membranes)

* ’flesh eating disease’ 30% mortality

QUINOLONES - CIPRO

Quinolones are synthetic, made first in 1987

They block bacterial DNA replication by stopping the re-coiling of new strands, make KNOTS instead

CIPROFLOXACIN: most active broad spectrum antibiotic available (Anthrax scare) Sales ~ 2B$/y

especially useful for lung infections, bones, urinary tract (oral or IV)

N N N

NH

F

O

HO2C

Related: Norfloxacin (Noroxin)Et in place of cyclopropyl

Some newer ones:

N N

HOOC F

N CH2NH2.HO3SMe

NOMe

O

N

HOOC F

N

O

NO

N

HOOC F

N

O

NH

F

F

Levofloxacin Trovafloxacin Gemifloxacin LEVAQUIN TROVAN

wide use for TB

Others: moxifloxacin; gatifloxacin; ofloxacinTrovan (2 x 200mg/day): In Canada about 360,000 pneumonia cases per year, still 7000 deaths

Some strains of staph which are Vancomyin and Methicillin resistant are now resistant to Cipro

Need to keep making newer classes:

2-Pyridones and Oxazolidinones

O N N

F

O

O

NHCOCH3N

O

F COOH

H2N

Linezolid (ZYVOXAM)

Antagonize enzymes: Bind the bacterial ribosome, shuts down protein synthesis

NEWEST APPROACH

EFFLUX PUMP BLOCKERS

Some resistant strains pump antibiotic out of the cell: these block that pump action

MICROCIDE have found a peptide that stops pseudomonas effluxing fluoroquinolones = drug ca. 8x more effective

2005: FDA granted fast track status to intravenous iclaprim for the treatment of complicated skin and skin structure infections (cSSSI) – resistant staph

ANTI-FUNGALS

N-C-O

S

O

OMe

MeO

Cl

O OMe

O

Tolnaftate, Tinactin, Pitrex Fungistop, Triactintopical only, inhibits steroid biosynthesis

Griseofulvin (Fulvicin, Grisovin, Grisactin) hair and nail infections

orally for ‘ringworm’

made by mould penicillin griseofulvin: disrupts the microtubules

Not if pregnant: teratogenNot with alcohol: tachycardia

NYSTATIN (mycostatin) especially for yeast (candida) infections (mouth, throat, vagina, underarms....)

Method of action: binds to ergosterol, the main component of the fungal cell membrane. If present in sufficient concentrations, it forms a pore in the membrane that leads to K+ leakage and death of the fungus.

(mammals do not have ergosterol-based cell membranes)

MONISTAT (miconazole)

Vaginal yeast infections: inhibits biosynthesis of triglycerides (fats), phospholipids, steroids and damages the fungus cell wall

Used topically as 2-3% cream

NN CH2 CH OCH2 Cl

Cl

Cl

Cl

OTHER ANTIFUNGALSTerbinafine [LAMISIL]Ketoconazole [NIZORAL] cream, shampoo, tabletsFluconazole [DIFLUCAN] capsulesItraconazole [SPORONOX] capsules, solutionClotrimazole [CANESTAN VAGINAL & TOPICAL] cream or insertsOxiconazole [OXIZOLE] cream, lotionChlorphenesin [MYCIL] cream

Selenium sulfide is often used in shampoos, sold as VERSEL (lotion)

N

terbinafine(an allylamine)

NNO

O

O

ON

Cl Cl

N

ketoconazole

OH

N

NF

F

N

N

N

N

Fluconazole

NN O

O

ON

Cl Cl

N

N

NN

N

O

Itraconazole

NN

Cl

Clotrimazole

Cl

Cl

N

N

Cl

Cl

Oxiconazole

Cl

O

OH

OH

Chlorphensin

H2NSO2

Cl

COOH

NHO

furosemide