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

ABSTRACT: Bacterial ?-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature ?-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D ?-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-? hydroxyethyl moiety to replace the original 6-? aminoacyl group. MPC-1 selectively inhibits class C ?-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 ?-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 ?-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 ?-lactamase inhibitors.

SUBMITTER: Pan X 

PROVIDER: S-EPMC5700298 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature