Pathogen resistance to β-lactam antibiotics is spreading. Of the various resistance mechanisms, the most effective involves the production of β-lactamases that hydrolyze β-lactam antibiotics. There are now over 840 known β-lactamases. One approach to overcoming resistance to β-lactam antibiotics is to find substances that can protect the β-lactam antibiotic from hydrolysis by β-lactamases. The first β-lactamase inhibitor to be used clinically was clavulanic acid from Streptomyces clavuligerus. When combined with traditional β-lactams such as amoxicillin and ticarcillin, clavulanic acid produces broad-spectrum antibiotic combinations effective against many β-lactamase-producing bacteria. Various other compounds have been found and developed as inhibitors. The success of clavulanic acid established β-lactamase inhibitors as one solution to the problem of β-lactam antibiotic-resistant bacteria. We are currently engaged in several aspects of the β-lactamase problem. In the search for new β-lactamase inhibitors, we employed ZINCPharmer to develop 3-D pharmacophores that can be further used to search the ZINC database of commercial compounds. Autodock Vina was used to perform in silico analyses of the potential binding of selected ZINC database compounds to the M. tuberculosis β-lactamase using protein structures from the PDB database. This work has resulted in the discovery of as yet unpublished sub-nanomolar inhibitors of the M. tuberculosis β-lactamase, PenSustain, our temporary name for this compound.

Discovery of a new class of β-lactamase inhibitors

251st National Meeting (2016)

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