1Drugs that Inhibit Cell wall synthesis

• Beta-lactams– Penicillin family– Cephalosporin family– Carbapenems and Monobactams– Β-lactamase inhibitors

• Vancomycin

• Bacitracin

• These drugs are bactericidal– Failure of the cell wall results in death

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3Penicillin Family

•AmdinocillinAmpicillinAugmentin*AzlocillinCarbenicillinCloxacillinCyclacillinDicloxacillinFloxacillin

AmoxicillinMethicillinMezlocillinNafcillinOxacillinPiperacillinSulbactam (beta-lactamase inhibitor)

TicarcillinTimentin*

http://www.wheelessonline.com/ortho/penicillin_family

* Combo with beta-lactamase inhibitor

4Development of Beta-lactam families

• Target different species– Not all drugs can pass through Gram – OM– “Penicillin binding proteins” (PBPs) vary – Specificity of beta-lactamases varies– Beta-lactam ring sensitive to hydrolysis; improved

acid stability for oral administration

• Thus drugs differ– In organisms that they affect– General pharmacokinetics, administration– Type and extent of resistance against

5Peptidoglycan Synthesis-1

• NAM and peptide with D-ala connected

• Attached to lipid carrier: bactoprenol-phosphate

• NAG added (UDP-NAG) to complete unit

• NAG-NAM-peptide transported through cell membrane to cell wall

6Peptidoglycan Synthesis-2

• new NAM-NAG unit attached, autolysins cut old wall

• crosslinking completed

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http://www.antiinfectieux.org/antiinfectieux/Assets/PLS/Beta-lactames/beta-lactames-mecanisme-action-2-600.gif http://www-organik.chemie.uni-wuerzburg.de/ak_engel/Sebastian/Bilder/diplom5.gif

D-Ala- D-Ala dipeptide

Beta-Lactam reaction with transpeptidase

10Consequences of mode of action

• Beta-lactam reacts with serine in active site– Irreversible binding, inactivates enzyme– Also inactivates drug, used up in reaction

• Target is in cell wall– External beta-lactamases destroy drug before target

is reached

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http://www.chemicalforums.com/index.php?page=molecules

Vancomycin, a glycopeptide

12Mechanism of vancomycin

vancomycin

Binds to peptide with high affinity via 5 hydrogen bonds

http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif

13Bacitracin

Peptide antibiotic

Isolated from Bacillus from a patient named Tracy.

With divalent cation, binds to bactoprenol-pyrophosphate, prevents dephosphorylation of carrier, blocks PG biosynthetic pathway.

http://smccd.net/accounts/case/biol230/bacitracin/bacitracin2.gif

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15Resistance to beta-lactams

• Beta-lactamases– Numerous types present among bacteria– Found on Gram – as well as Gram +– Coded for plasmids or by chromosomal genes– Some sensitive to beta-lactamase inhibitors, some

not

• Resistance in Gram - : failure to reach target– Passage through OM is through porins– Although porins are not highly selective, some

drugs cannot pass or the porins become mutated

16Resistance to beta-lactams-2

• Failure to bind to target– Wide variety of bacteria, wide assortment of PBPs– Mutations occur in PBP genes

• About MRSA– Staph aureus originally susceptible to penicillin,

1940s; by 1950s, no longer– About 40% of Staph aureus now resistant to

methicillin and other beta-lactamse resistant drugs– Has acquired a gene for a PBP that poorly binds

beta-lactams, causing resistance

17Resistance to vancomycin

• A cluster of genes that senses the presence of vancomycin, activates an enzyme that replaces the D-ala-D-ala dipeptide with D-ala-D-lactate.– Interesting evolutionary history– Gene cluster probably originated with producing

streptomyces– Known to be present in Enterococci, probably

passed by conjugation to Staph aureus.– http://www.medscape.com/viewarticle/473156

proposes spread of resistance in animal feed

18Pharmacokinetics

• Beta-lactams differ greatly in – Route of administration (oral absorption)– Binding to serum proteins– Metabolism and extent of renal excretion

• Tend to be excreted unchanged (good for treatment of urinary tract infections)

• Benzathine penicillin, im injection– Half life of 14 days– Mainstay of health clinics for treatment of syphilis

19About combinations

• Beta-lactamase inhibitors– Clavulanate, sulbactam, and tazobactam– Some have weak antibiotic activity alone– Bind to beta-lactamases and inhibit them– Beta-lactamase inhibitors paired with beta-lactam

antibiotics which then do the heavy lifting

• Typical example– Clavulanate + amoxicillin = Augmentin

20Toxicity

• Beta-lactams show wide range– Diarrhea and other GI problems are most common

• Problems with upsetting normal ecology• Most significant danger: pseudomembranous

colitis caused by Clostridium difficile– Delayed type hypersensitivity much more likely than

immediate type (IgE), fortunately

21Toxicity-2

• Vancomycin– Hypersensitivity reactions with rash and

hypotension– Ototoxicity, phlebitis

• Bacitracin– Topically administered, few problems– Cannot be taken internally because of inhibition of

sterol synthesis, nephrotoxicity