Scaffold Simplification Yields Potent Antibacterial Agents That Target Bacterial Topoisomerases

TL;DR

Scientists simplified a compound's structure to create powerful antibacterial agents that target DNA replication enzymes in bacteria.

Contribution

A novel series of simplified antibacterial compounds with potent activity and a defined DNA-targeting mechanism was developed.

Findings

Simplified analogs showed 10-100 times better antibacterial activity than ciprofloxacin against ESKAPE pathogens.

Compounds inhibit bacterial topoisomerase I and DNA gyrase, disrupting DNA replication.

Moderate human cell toxicity was observed, but with sufficient selectivity for further drug development.

Abstract

This work describes the lead optimization of a promising class of antibacterial compounds, derived from a previously reported N-[4-(4-fluorophenoxy)phenyl]-6-(methylsulfonyl)-2,6-diazaspiro [3.4]octane-8-carboxamide (LK1819), through systematic scaffold simplification. A novel series of amide derivatives were designed and synthesized, exploring key structural variations, including the replacement of the diphenyl ether core with a biphenyl system. All compounds were evaluated for in vitro antibacterial activity against the ESKAPE panel of pathogens. The most potent simplified analogs demonstrated exceptional, broad-spectrum activity, with minimum inhibitory concentrations (MICs) that were 10 to 100 times lower than the control antibiotic ciprofloxacin against many strains. Mechanistic studies using a reporter system and enzymatic assays revealed that the compounds do not inhibit protein synthesis but disrupt DNA replication, exhibiting a dose-dependent inhibitory effect on bacterial topoisomerase I and DNA gyrase. The compounds showed moderate toxicity against human cell lines, consistent with their DNA-targeting mechanism, but cytotoxicity assays indicated a sufficient selectivity window. We conclude that scaffold simplification successfully yielded highly potent antibacterial agents with a defined mechanism of action, presenting a promising foundation for further development as antibiotics and potentially as anticancer agents.

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