Mistry Tina L, Truong Lena, Ghosh Arun K, Johnson Michael E, Mehboob Shahila
Center for Biomolecular Sciences, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
Department of Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
ACS Infect Dis. 2017 Jan 13;3(1):54-61. doi: 10.1021/acsinfecdis.6b00123. Epub 2016 Oct 27.
The enoyl-ACP reductase (FabI) enzyme is a well validated target for anti-staphylococcal drug discovery and development. With the goal of finding alternate therapeutics for drug-resistant strains of Staphylococcus aureus, such as methicillin-resistant S. aureus (MRSA), our previously published series of benzimidazole-based inhibitors of the FabI enzyme from Francisella tularensis (FtFabI) have been evaluated against FabI from S. aureus (SaFabI). We report here the preliminary structure-activity relationship of this series and the prioritization of compounds toward lead optimization. Mutational studies have identified key residues that contribute toward stabilizing the inhibitors in the active site of FabI. Mutations that do not significantly impact enzyme function but destabilize inhibitor binding are more likely to occur in nature as organisms evolve to evade the action of antibiotics leading to resistance. Identifying these residues provides guidance for minimizing susceptibility to resistance. Additionally, we have identified compounds that elicit antibacterial activity through off-target effects and observe that close analogs can display differing modes of action (on-target vs off-target) and need to be individually evaluated early on to prioritize compounds for lead optimization. Overall, our data suggest that the benzimidazole scaffold is a promising scaffold for anti-staphylococcal drug development.
烯酰-ACP还原酶（FabI）是抗葡萄球菌药物研发中一个经过充分验证的靶点。为了寻找针对耐药金黄色葡萄球菌菌株（如耐甲氧西林金黄色葡萄球菌，MRSA）的替代疗法，我们之前发表的一系列基于苯并咪唑的土拉弗朗西斯菌FabI酶（FtFabI）抑制剂已针对金黄色葡萄球菌的FabI（SaFabI）进行了评估。我们在此报告该系列的初步构效关系以及化合物用于先导优化的优先级。突变研究确定了有助于使抑制剂在FabI活性位点稳定的关键残基。那些对酶功能没有显著影响但会破坏抑制剂结合的突变，在生物体进化以逃避抗生素作用导致耐药性的过程中更有可能在自然界中出现。识别这些残基为降低耐药易感性提供了指导。此外，我们还鉴定出了通过脱靶效应产生抗菌活性的化合物，并观察到紧密类似物可表现出不同的作用模式（靶向与脱靶），需要在早期就对其进行单独评估，以便为先导优化确定化合物的优先级。总体而言，我们的数据表明苯并咪唑支架是抗葡萄球菌药物开发的一个有前景的支架。
