Modified penicillin molecule with carbapenem-like stereochemistry specifically inhibits class C β-lactamases

Xuehua Pan, Yunjiao He, Tianfeng Chen, Kin Fai Chan, Yanxiang Zhao

Research output: Journal article publicationJournal articleAcademic researchpeer-review

2 Citations (Scopus)

Abstract

Bacterial β-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and “opening” their signature β-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D β-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by “grafting” carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-β amino-acyl group. MPC-1 selectively inhibits class C β-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is ~2 to 5 times higher than that for clinically used β-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A β-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel β-lactamase inhibitors.
Original languageEnglish
Article numbere01288
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • Carbapenem-like
  • Class C β-lactamase
  • β-lactamase inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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