Sheppard Jordan G, McAleer Jeremy P, Saralkar Pushkar, Geldenhuys Werner J, Long Timothy E
Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA.
Eur J Med Chem. 2018 Jan 1;143:1185-1195. doi: 10.1016/j.ejmech.2017.10.018. Epub 2017 Oct 12.
A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S-alkyl chains of 7-9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as antibiotic adjuvants in combination therapy of S. aureus infections with reduced vancomycin susceptibility.
对一个由19种合成吡啶基二硫化物组成的化学文库进行了评估,该文库模拟大蒜素的化学反应性,检测其对一组致病细菌的抗菌活性。革兰氏阳性菌,包括万古霉素中介和耐万古霉素金黄色葡萄球菌(VISA、VRSA),对具有7至9个碳原子的S-烷基链类似物表现出最高水平的敏感性。进一步的生物学研究表明,二硫化物与万古霉素对VRSA具有协同作用,可导致金黄色葡萄球菌生物膜分散,细胞毒性低,并减缓金黄色葡萄球菌的代谢。最终分析表明,吡啶基二硫化物代表了一类新型的基于机制的抗菌剂,在治疗对万古霉素敏感性降低的金黄色葡萄球菌感染的联合疗法中,有作为抗生素佐剂的潜在应用。