1. Drugs 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

3. Development of Beta-lactam families
Target different species
Not all drugs can pass through Gram – OM
“Penicillin binding proteins” (PBPs) vary
Possession 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

4. Peptidoglycan Synthesis
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
new NAM-NAG unit attached, autolysins cut old wall
crosslinking completed

7. Beta-Lactam reaction with transpeptidase
D-Ala- D-Ala dipeptide

8. Consequences of mode of action
Enzyme 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

9. Vancomycin, a glycopeptide

10. Mechanism of vancomycin
Binds to peptide with high affinity via 5 hydrogen bonds

11. Bacitracin 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.

13. Resistance 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

14. Resistance 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

15. Resistance 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.
proposes spread of resistance in animal feed

16. Pharmacokinetics 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

17. About combinations Beta-lactamase inhibitors Typical example
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

18. Toxicity 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

19. Toxicity-2 Vancomycin Bacitracin
Hypersensitivity reactions with rash and hypotension
Ototoxicity, phlebitis
Bacitracin
Topically administered, few problems
Cannot be taken internally because of inhibition of sterol synthesis, nephrotoxicity