Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Drug Dev Res. 2019 Feb;80(1):171-178. doi: 10.1002/ddr.21507. Epub 2018 Dec 19.
Staphylococcus aureus is a WHO Priority II pathogen for its capability to cause acute to chronic infections and to resist antibiotics, thus severely impacting healthcare systems worldwide. In this context, it is urgently desired to discover novel molecules to thwart the continuing emergence of antimicrobial resistance. Disulphide containing small molecules has gained prominence as antibacterials. As their conventional synthesis requires tedious synthetic procedure and sometimes toxic reagents, a green and environmentally benign protocol for their synthesis has been developed through which a series of molecules were obtained and evaluated for antibacterial activity against ESKAPE pathogen panel. The hit compound was tested for cytotoxicity against Vero cells to determine its selectivity index and time-kill kinetics was determined. The activity of hit was determined against a panel of S. aureus multi-drug resistant clinical isolates. Also, its ability to synergize with FDA approved drugs was tested as was its ability to reduce biofilm. We identified bis(2-bromophenyl) disulphide (2t) as possessing equipotent antimicrobial activity against S. aureus including MRSA and VRSA strains. Further, 2t exhibited a selectivity index of 25 with concentration-dependent bactericidal activity, synergized with all drugs tested and significantly reduced preformed biofilm. Taken together, 2t exhibits all properties to be positioned as novel scaffold for anti-staphylococcal therapy.
金黄色葡萄球菌是世界卫生组织（WHO）列为优先级 2 的病原体，因为它能够引起急性到慢性感染，并对抗生素产生耐药性，从而严重影响全球的医疗保健系统。在这种情况下，迫切需要发现新的分子来阻止抗菌药物耐药性的持续出现。含二硫键的小分子作为抗菌药物已经引起了关注。由于它们的常规合成需要繁琐的合成步骤和有时使用有毒试剂，因此已经开发出一种绿色环保的合成方法，通过该方法获得了一系列分子，并对其针对 ESKAPE 病原体组的抗菌活性进行了评估。对候选化合物进行了抗vero 细胞的细胞毒性测试，以确定其选择性指数，并确定时间杀伤动力学。对候选化合物进行了针对一系列耐多药金黄色葡萄球菌临床分离株的活性测试。此外，还测试了它与 FDA 批准药物的协同作用以及减少生物膜的能力。我们确定双（2-溴苯基）二硫化物（2t）对金黄色葡萄球菌（包括 MRSA 和 VRSA 菌株）具有等效的抗菌活性。此外，2t 表现出 25 的选择性指数，具有浓度依赖性杀菌活性，与所有测试的药物协同作用，并显著减少了已形成的生物膜。综上所述，2t 具有作为新型抗葡萄球菌治疗药物的所有特性。
