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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Interactions of β-Lactamases with Antibiotics and Inhibitors

Beta-lactams remain the single most important antibiotic class. Beta-lactamases are hydrolytic enzymes that inactivate the antibiotic by degrading the scissile amide bond of the four-membered beta-lactam ring, and are the most prevalent resistance mechanism in Gram-negative bacterial pathogens responsible for a variety of opportunistic infections. To date more than 4000 beta-lactamases have been identified in environmental and clinical bacterial strains. These enzymes vary widely in their activity against the different beta-lactam classes (principally penicillins, cephalosporins and carbapenems) and their susceptibility towards inhibitors that include beta-lactam- (clavulanic acid) and non-beta-lactam (diazabicyclooctane; boronate) based agents. Beta-lactamases also divide into two groups: active-site serine enzymes (classes A, C and D) and zinc metallo-enzymes (class B) that differ fundamentally in structure and mechanism.

Our research focuses on interactions of beta-lactamases with carbapenems, the most recently introduced beta-lactams and key antibiotics for infections by Gram-negative bacteria. Carbapenems escape hydrolysis by most serine beta-lactamases as the 6α-hydroxyethyl substituent and tautomerization within the fused pyrroline ring system are together proposed to retard breakdown of the covalent acylenzyme intermediate; carbapenem hydrolysis (carbapenemase activity) is restricted to a select few serine enzymes. In contrast, metallo-beta-lactamases efficiently hydrolyze carbapenems. We have investigated carbapenem hydrolysis by both serine carbapenemases and metallo-beta-lactamases, combining high-resolution crystallographic methods and high-level computational (molecular dynamics and quantum mechanics/molecular mechanics (QM/MM)) approaches to seek to identify the requirements for hydrolysis of these substrates. I will further describe the interactions of both serine and metallo-beta-lactamases with a range of inhibitors, extending from compounds in clinical use to experimental compound series aimed at expanding inhibition to include the metallo-beta-lactamases against which current agents are ineffective.

Catherine L. Tooke 1,2
Philip Hinchliffe 1
Ramya Salimraj 1
Karina Calvopiña 1,
Viivi H.A. Hirvonen 2
Matthew B. Avison 1
Marc W. van der Kamp 2,3
Adrian J. Mulholland 2
James Spencer 1

1 School of Cellular and Molecular Medicine
University of Bristol
Bristol BS8 1TD, U.K

2 School of Chemistry
University of Bristol
Bristol BS8 1TS, U.K.

3 School of Biochemistry
University of Bristol
Bristol BS8 1TD, U.K.

Ph: (44) 117 331 2084
Fax: (44) 117 331 2091
E-mail: Jim.Spencer@bristol.ac.uk