De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region

By 2050, it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, more deaths than cancer, costing the world economy $100 trillion. Clearly, strategies to address this problem are essential 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 binding site, resistance is not yet documented. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by a published thiophene-based allosteric inhibitor. This series was evaluated in vitro against Escherichia coli DNA gyrase and E. coli topoisomerase IV with the most potent compounds exhibiting IC50 values towards the low micromolar range for DNA gyrase and only similar to 2-fold less active against topoisomerase IV. The structure-activity relationships reported herein suggest insights to further exploit this allosteric site, offering a pathway to overcome developing fluoroquinolone resistance.

Automated summary

By 2050, antimicrobial resistance is likely to cause 10 million global deaths annually, resulting in a massive economic burden. However, the discovery of a new medicinal chemistry strategy targeting a different binding site on DNA gyrase may provide a way to overcome this problem. Through computer-based molecular design methods, a series of novel compounds were synthesized and evaluated for their activity. The reported structure-activity relationships offer important insights for further exploration of this new binding site.