Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C β-Lactamases

Abstract

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 aminoacyl 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.