Moore Jonah A, Meakin Michaela, Earl Mikaela H, Kummer Tiffany M, McAleer Jeremy P, Long Timothy E
Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, One John Marshall Drive, Huntington, WV 25755, USA.
Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, One John Marshall Drive, Huntington, WV 25755, USA; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, One John Marshall Drive, Huntington, WV 25755, USA.
J Glob Antimicrob Resist. 2020 Sep;22:283-289. doi: 10.1016/j.jgar.2020.03.014. Epub 2020 Apr 1.
Vancomycin is a first-line antibiotic for the treatment of invasive infections in humans caused by methicillin-resistant Staphylococcus aureus (MRSA). Based on the premise that antibiotic combinations can exhibit synergistic and antagonistic interactions, medications used for the treatment of infection and other medical conditions were evaluated for their ability to alter MRSA susceptibility to vancomycin.
A chemical library comprised of 1237 pharmacological agents was evaluated in a 96-well plate format for its ability to inhibit MRSA growth in combination with half the minimum inhibitory concentration (MIC) of vancomycin. Caspofungin and tolcapone were further assessed for synergistic potential by isobologram (checkerboard) and flow cytometric analysis. In addition, the antibacterial activity spectrum and effects of growth conditions of the two drugs were delineated by MIC determination.
The study identified 17 nonantibiotic library members with synergistic or additive potential, including caspofungin and tolcapone. Further analyses revealed that the respective medications for invasive candidiasis and Parkinson disease were bactericidal and bacteriostatic inhibitors of S. aureus growth. Flow cytometric analysis of viability further demonstrated that caspofungin in combination with vancomycin increased MRSA cell death in an additive manner, whereas tolcapone appeared to suppress the bactericidal action of vancomycin.
Overall, this proof of concept study concluded that nonantibiotic drugs can alter the pharmacodynamic properties of vancomycin, with potential clinical implications in patients with a MRSA infection receiving medications for other medical conditions.
万古霉素是治疗由耐甲氧西林金黄色葡萄球菌（MRSA）引起的人类侵袭性感染的一线抗生素。基于抗生素组合可呈现协同和拮抗相互作用这一前提，对用于治疗感染及其他病症的药物改变MRSA对万古霉素敏感性的能力进行了评估。
采用96孔板形式对由1237种药理剂组成的化学文库进行评估，以确定其与万古霉素最低抑菌浓度（MIC）的一半联合时抑制MRSA生长的能力。通过等效线图（棋盘法）和流式细胞术分析进一步评估卡泊芬净和托卡朋的协同潜力。此外，通过MIC测定描绘了这两种药物的抗菌活性谱及生长条件的影响。
该研究确定了17种具有协同或相加潜力的非抗生素文库成员，包括卡泊芬净和托卡朋。进一步分析表明，用于侵袭性念珠菌病和帕金森病的相应药物分别是金黄色葡萄球菌生长的杀菌和抑菌抑制剂。活力的流式细胞术分析进一步表明，卡泊芬净与万古霉素联合以相加方式增加了MRSA细胞死亡，而托卡朋似乎抑制了万古霉素的杀菌作用。
总体而言，这项概念验证研究得出结论，非抗生素药物可改变万古霉素的药效学特性，对接受其他病症治疗药物的MRSA感染患者具有潜在临床意义。
