Structure Activity Relationship

The pharmacophore of the p-lactams is a highly reactive four-membered azetidi-none ring which is generally fused to a five- or six-membered ring (Table 7). There

Table 7 Basic structures of clinically relevant b-lactams and their pharmacologic properties

b-lactam

Pharmacophore

Spectrum of

Inactivation

Adverse effects

class

activity

zy n— o i

Gram-positives

Classical

Diarrhea,

b-lactamases,

hypersensitivity,

carbapenemases

anaphylaxis,

o^oih

pseudomembranous colitis, yeast infections

Cephems

R M

Gram-negatives

Extended-

Diarrhea,

spectrum

hypersensitivity,

b-lactamases,

pseudomembranous

O^OH

carbapenemases, cephalosporinases

colitis, yeast infections

Carbapenems

H° H

Gram-positives,

Renal

Diarrhea, anaphylaxis,

O i

Gram-negatives,

dehydropeptidase,

pseudomembranous

anaerobes

carbapenemases

colitis,

O^OH

nephrotoxicity,

J-K ,9

neurotoxicity

Mono-

Select Gram-

Extended-

Diarrhea,

bactams

negatives

spectrum

pseudomembranous

b-lactamases,

colitis, yeast infections

_o' oh carbapenemases o X

_o' oh carbapenemases is an absolute requirement for the p-lactam ring and a carboxylic acid on the fused ring (or an electron withdrawing moiety such as the sulfonyl as in monobactams). An amide a to the p-lactam ring is preferred. Conformationally, this core resembles the acyl-d-alanyl-d-alanine moiety of the natural substrate. The serine nucleophile in the enzyme active site attacks the electrophilic carbonyl of the p-lactam amide leading to ring opening and irreversible acylation of the enzyme.

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