Competitive fitness of essential gene knockdowns reveals a broad-spectrum antibacterial inhibitor of the cell division protein FtsZ.

Competitive fitness of essential gene knockdowns reveals a broad-spectrum antibacterial inhibitor of the cell division protein FtsZ. Antimicrob Agents Chemother. 2018 Oct 08;: Authors: Hogan AM, Scoffone VC, Makarov V, Gislason AS, Tesfu H, Stietz MS, Brassinga AKC, Domaratzki M, Li X, Azzalin A, Biggiogera M, Riabova O, Monakhova N, Chiarelli LR, Riccardi G, Buroni S, Cardona ST Abstract To streamline elucidation of antibacterial compounds' mechanism of action, comprehensive high-throughput assays interrogating multiple putative targets are necessary. However, current chemogenomic approaches for antibiotic target identification have not fully utilized the multiplexing potential of next-generation sequencing. Here, we used Illumina sequencing of transposon insertions to track the competitive fitness of a Burkholderia cenocepacia library containing essential gene knockdowns. Using this method, we characterized a novel benzothiadiazole derivative, 10126109 (C109) with antibacterial activity against B. cenocepacia, for which whole-genome sequencing of low-frequency, spontaneous drug-resistant mutants had failed to identify the drug target. By combining identification of hypersusceptible mutants and morphology screening, we show that C109 targets cell division. Furthermore, fluorescence microscopy of bacteria harboring GFP-cell division protein fusions revealed that C109 prevents divisome formation by altering the localization of the ess...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research