Singh Vishakha, Dhankhar Poonam, Dalal Vikram, Tomar Shailly, Golemi-Kotra Dasantila, Kumar Pravindra
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee247667, India.
Department of Biology, York University, 4700 Keele Street, TorontoM3J 1P3, Ontario, Canada.
ACS Omega. 2022 Oct 18;7(43):38448-38458. doi: 10.1021/acsomega.2c03671. eCollection 2022 Nov 1.
is considered as one of the most widespread bacterial pathogens and continues to be a prevalent cause of mortality and morbidity across the globe. FmtA is a key factor linked with methicillin resistance in . Consequently, new antibacterial compounds are crucial to combat resistance. Here, we present the virtual screening of a set of compounds against the available crystal structure of FmtA. The findings indicate that gemifloxacin, paromomycin, streptomycin, and tobramycin were the top-ranked potential drug molecules based on the binding affinity. Furthermore, these drug molecules were analyzed with molecular dynamics simulations, which showed that the identified molecules formed highly stable FmtA-inhibitor(s) complexes. Molecular mechanics Poisson-Boltzmann surface area and quantum mechanics/molecular mechanics calculations suggested that the active site residues (Ser127, Lys130, Tyr211, and Asp213) of FmtA are crucial for the interaction with the inhibitor(s) to form stable protein-inhibitor(s) complexes. Moreover, fluorescence- and isothermal calorimetry-based binding studies showed that all the molecules possess dissociation constant values in the micromolar scale, revealing a strong binding affinity with FmtA, leading to stable protein-drug(s) complexes. The findings of this study present potential beginning points for the rational development of advanced, safe, and efficacious antibacterial agents targeting FmtA.
被认为是分布最广泛的细菌病原体之一，并且仍然是全球范围内导致死亡和发病的普遍原因。FmtA是与耐甲氧西林相关的关键因素。因此，新型抗菌化合物对于对抗耐药性至关重要。在此，我们针对FmtA的可用晶体结构展示了一组化合物的虚拟筛选。研究结果表明，基于结合亲和力，吉米沙星、巴龙霉素、链霉素和妥布霉素是排名靠前的潜在药物分子。此外，对这些药物分子进行了分子动力学模拟分析，结果显示所鉴定的分子形成了高度稳定的FmtA-抑制剂复合物。分子力学泊松-玻尔兹曼表面积和量子力学/分子力学计算表明，FmtA的活性位点残基（Ser127、Lys130、Tyr211和Asp213）对于与抑制剂相互作用形成稳定的蛋白质-抑制剂复合物至关重要。此外，基于荧光和等温滴定量热法的结合研究表明，所有分子的解离常数均在微摩尔范围内，表明与FmtA具有很强的结合亲和力，从而形成稳定的蛋白质-药物复合物。本研究结果为合理开发针对FmtA的先进、安全且有效的抗菌剂提供了潜在的起点。
