Sheppard Jordan G, Long Timothy E
Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV 25755, United States.
Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV 25755, United States; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
Bioorg Med Chem Lett. 2016 Nov 15;26(22):5545-5549. doi: 10.1016/j.bmcl.2016.10.002. Epub 2016 Oct 4.
Thiolated fluoroquinolones were synthesized from ciprofloxacin and evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA) exhibited the highest level of increased sensitivity toward ciprofloxacin bound with a N-propylthio substituent. Evidence was found that the antibiotics form disulfides with low molecular weight thiols in bacteria and potentiate generation of cytosolic reactive oxygen species (ROS). In final analysis, the enhanced anti-MRSA activity of thiolated fluoroquinolones was attributed to increased cell permeability and reaction with cytosolic thiols that yields an inactive disulfide metabolite and the parent drug ciprofloxacin as an inhibitor of DNA synthesis.
硫醇化氟喹诺酮类药物由环丙沙星合成，并针对一组病原菌评估了其抗菌活性。包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的革兰氏阳性菌对与N-丙基硫代取代基结合的环丙沙星表现出最高水平的敏感性增加。有证据表明，这些抗生素在细菌中与低分子量硫醇形成二硫键，并增强细胞溶质活性氧（ROS）的生成。最终分析表明，硫醇化氟喹诺酮类药物增强的抗MRSA活性归因于细胞通透性增加以及与细胞溶质硫醇的反应，该反应产生无活性的二硫代谢物和作为DNA合成抑制剂的母体药物环丙沙星。
