Cell wall inhibitors

Cell wall as target

Unique to bacteria

Providing selective target

Made of peptidoglycan

NAG-NAM monomers joined by glycosidic bonds

Cross linked via amino acid side chain

Via transpeptidase → PBP

Ideal Antimicrobial properties?

Specific

Selective

Bactericidal

B lactams types

5 membered ring with sulphur → penicillin

6 membered → cephalosporin

5 membered no sulphur → carbapenems

4 membered ring → monobactam

B lactam mechanism

Enzyme negatively charged O binds to delta positive carbonyl in B lactam ring which forms an stable acyl-enzyme intermediate

Reacts with active site of nucleophile usually serine

Irreversible reaction

B lactam properties?

Thought to mimic D-Ala-D-Ala dipeptide involved in crosslinking of peptidoglycan

B lactam ring is highly strained

Making B lactam bond an electrophile

Resistance to B lactams

Target modification can’t bind to PBPs

Amidases removes penicillin side chain so it becomes a charged amine reducing ability to bond

B-lactamases → allows the slow hydrolysis of the acyl enzyme complex to happen rapidly

Types of B lactamases?

A Penicillinase TEM 1/2 → plasmids

B metallo B lactamases NDM1

C Cephalosporinases → encoded in gene

D Extended spectrum B lactamses

Probably evolved from PBPs due to antibiotic selective pressures

Strategies to over come B lactamases?

Develop antibiotics resistant to hydrolysis

Problems

Discovered most antibiotics already

Patients failing to take full course

Careful use community

How are new antibiotics discovered?

Natural product screening

Manipulation of biosynthesis pathway

Engineering of biosynthetic pathway using genetic techniques

B lactams 3 modes of action

Direct

Bind and inhibit transpeptidases (PBP)

Get incorporated into peptide side chain

Indirect

Stimulate autolysins