Biological and Medicinal Chemistry

De Novo Design of Type II Topoisomerase Inhibitors as Potential Antimicrobial Agents Targeting a Novel Binding Region

Authors

Abstract

By 2050 it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, costing the world economy $100 trillion. Clearly, strategies to address this problem are required as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy, as this site is distinct from the fluoroquinolone-DNA site binding site. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by the published thiophene allosteric inhibitor. This series was evaluated in vitro against E. coli DNA gyrase, exhibiting IC50 values in the low micromolar range. The structure-activity relationship reported herein suggests insights to further exploit this allosteric site, offering a pathway to overcome fluoroquinolone resistance.

Content

Thumbnail image of Orritt DNA gyrase inhibitors final draft 12 July.pdf

Supplementary material

Thumbnail image of Orritt DNA gyrase inhibitors SI Final draft 12 July.pdf
De Novo Design of Type II Topoisomerase Inhibitors as Potential Antimicrobial Agents Targeting a Novel Binding Region
Chemical and biochemical methods