Beta-lactamases are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems (ertapenem). Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. Bacteria that produce carbapenemases are often referred to in the news media as superbugs" because infections caused by them are difficult to treat. Recently, with the use of virtual screening and docking to identify and characterize novel beta-lactamase inhibitors as potential therapeutics to treat to treat a broad spectrum of Gram-positive and Gram-negative bacteria has been reported in the literature. Hence, there is interest in the development of new and improved beta-lactamase inhibitors. Here, we describe the use of an iterative in silico and in vitro work-flow for identifying novel beta-lactamase inhibitors. The first in silico arm of the work-flow involves the use of library design, virtual screening, docking, and consensus scoring to identify predicted hit compounds. The in vitro arm involves rapid assaying of predicted hits in an optimized beta-lactamase assay. Confirmed hits are passed into the second (optimization) in silico arm which involves ligand-based screening, docking, and consensus scoring. We have added more criteria to our in silico docking model such as libraries of sub-structures of known substrates and inhibitors. Currently we have identified ractopamine as a µM inhibitor, Pharmaceutical Hit and are performing rational based drug design/Structure Activity Relationships. Preliminary results appear encouraging, providing hope that a novel beta-lactamases drug candidate will be identified and that our computational work-flow will prove useful on other targets.

Integrated screening for beta-lactamases inhibitors identification of pharmaceutical hits and lead optimization

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.