Infectious Disease Research Institute, Seattle, Washington, USA.
Seattle Children's Research Institute, Seattle, Washington, USA.
Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0262220. doi: 10.1128/AAC.02622-20.
To combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series was previously identified as an inhibitor of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram-negative bacterium Escherichia coli . We isolated resistant mutants of E. coli and subjected them to whole-genome sequencing. We found mutations in the enoyl acyl carrier protein FabI. Mutations mapped around the active center site located close to the cofactor binding site. This site partially overlaps with the binding pocket of triclosan, a known FabI inhibitor. Similar to triclosan, the physical interaction of the benzoxaborole with FabI was dependent on the cofactor NAD. Identification of the putative target of this compound in E. coli provides scope for further development and optimization of this series for Gram-negative pathogens.
为了应对抗菌药物耐药性感染的迫在眉睫的危机，我们迫切需要发现新的抗菌药物和药物靶点。苯并恶唑酮系列化合物以前被鉴定为抑制分枝杆菌生长的化合物。在这里，我们证明苯并恶唑酮也对革兰氏阴性菌大肠杆菌有效。我们分离了大肠杆菌的耐药突变体，并对其进行了全基因组测序。我们发现了烯酰基辅酶 A 蛋白 FabI 中的突变。突变位于靠近辅因子结合位点的活性中心附近。该位点与三氯生（一种已知的 FabI 抑制剂）的结合口袋部分重叠。与三氯生类似，苯并恶唑酮与 FabI 的物理相互作用依赖于辅因子 NAD。该化合物在大肠杆菌中的靶标鉴定为进一步开发和优化该系列化合物以用于革兰氏阴性病原体提供了空间。
