Convergent Biosynthetic Pathways to β-lactam Antibiotics

Overview

Journal Curr Opin Chem Biol

Publisher Elsevier

Specialty Biochemistry

Date 2016 Oct 4

PMID 27693891

Citations 27

Authors

Craig A Townsend

Affiliations

Soon will be listed here.

Abstract

Five naturally-occurring families of β-lactams have inspired a class of drugs that constitute >60% of the antimicrobials used in human medicine. Their biosynthetic pathways reveal highly individualized synthetic strategies that yet converge on a common azetidinone ring assembled in structural contexts that confer selective binding and inhibition of d,d-transpeptidases that play essential roles in bacterial cell wall (peptidoglycan) biosynthesis. These enzymes belong to a single 'clan' of evolutionarily distinct serine hydrolases whose active site geometry and mechanism of action is specifically matched by these antibiotics for inactivation that is kinetically competitive with their native function. Unusual enzyme-mediated reactions and catalytic multitasking in these pathways are discussed with particular attention to the diverse ways the β-lactam itself is generated, and more broadly how the intrinsic reactivity of this core structural element is modulated in natural systems through the introduction of ring strain and electronic effects.

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