Grossman Trudy H, Shoen Carolyn M, Jones Steven M, Jones Peter L, Cynamon Michael H, Locher Christopher P
Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, New York, USA.
Antimicrob Agents Chemother. 2015 Mar;59(3):1534-41. doi: 10.1128/AAC.04271-14. Epub 2014 Dec 22.
Previous studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against Mycobacterium tuberculosis in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited M. tuberculosis growth in broth culture (MIC, 19 μg/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. When M. tuberculosis was cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 μg/ml) in the growth inhibition of M. tuberculosis and demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log10 reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted.
先前的研究表明，抑制外排泵可增强结核病治疗效果。在本研究中，我们使用替莫达（原VX - 853）来确定这种外排泵抑制剂在体外和体内联合研究中是否能增强抗结核药物对结核分枝杆菌的效力。单独使用时，替莫达在肉汤培养中对结核分枝杆菌生长的抑制作用较弱（最低抑菌浓度，19μg/ml）；然而，在与利福平、贝达喹啉和氯法齐明的联合药物研究中它显示出协同作用，但与其他抗结核药物则没有。当结核分枝杆菌在宿主巨噬细胞中培养时，替莫达对结核分枝杆菌生长抑制作用增加了约10倍（50%抑制浓度，1.9μg/ml），并与利福平、莫西沙星和贝达喹啉显示出协同作用。在肺结核感染小鼠模型中，替莫达增强了利福平和异烟肼的疗效，与每种药物单独使用时相比，肺部细菌载量分别降低了1.0和0.4个对数10。此外，在长期慢性感染的小鼠模型中，用利福平、异烟肼和替莫达联合治疗时，替莫达降低了复发感染的可能性。尽管替莫达对血浆和肺中利福平的药代动力学没有影响，但它确实增加了贝达喹啉的血浆暴露量。这些数据表明，替莫达的抗分枝杆菌药物增效活性是复杂且依赖药物的，涉及细菌和宿主靶向机制。有必要进一步研究与替莫达联合使用时抗分枝杆菌药物和候选药物效力的提高情况。
