5XHR

Crystal structure of P99 beta-lactamase in complex with a penicillin derivative MPC-1

Summary for 5XHR

• Entry DOI: 10.2210/pdb5xhr/pdb
• Descriptor: Beta-lactamase, (2~{R},4~{S})-5,5-dimethyl-2-[(2~{S},3~{R})-3-oxidanyl-1-oxidanylidene-5-thiophen-2-yl-pentan-2-yl]-1,3-thiazolidine-4-carboxylic acid (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: Enterobacter cloacae
• Cellular location: Periplasm : P05364
• Total number of polymer chains: 1
• Total formula weight: 39911.52

Authors

Pan, X.,Zhao, Y. (deposition date: 2017-04-24, release date: 2017-09-27, Last modification date: 2024-10-30)

Primary citation

Pan, X.,He, Y.,Chen, T.,Chan, K.F.,Zhao, Y.
Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C beta-Lactamases
Antimicrob. Agents Chemother., 61:-, 2017

PubMed 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 conformation of hydrogen atoms at C-5 and C-6 instead of , 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.

PubMed: 28971874
DOI: 10.1128/AAC.01288-17

Experimental method

X-RAY DIFFRACTION (1.8 Å)