Adams Kristin N, Szumowski John D, Ramakrishnan Lalita
Department of Microbiology.
Department of Medicine, Division of Infectious Diseases.
J Infect Dis. 2014 Aug 1;210(3):456-66. doi: 10.1093/infdis/jiu095. Epub 2014 Feb 14.
Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.
药物耐受性可能是缩短结核病治疗疗程的一个重要障碍。我们之前认为结核分枝杆菌外排泵Rv1258c介导巨噬细胞诱导的对利福平的耐受性及细胞内生长。在本研究中，我们用药物敏感和耐药的结核分枝杆菌菌株感染人巨噬细胞样细胞系THP-1，发现对大多数抗结核药物产生了耐受性，包括新型药物莫西沙星、PA-824、利奈唑胺和贝达喹啉。临床上用于其他适应症的多种外排泵抑制剂可逆转对异烟肼和利福平的耐受性，并减缓细胞内生长。此外，维拉帕米可降低对贝达喹啉和莫西沙星的耐受性。维拉帕米的R异构体及其代谢产物去甲维拉帕米的钙通道阻滞活性显著较低，但在抑制巨噬细胞诱导的药物耐受性方面与维拉帕米具有相似的活性。我们发现维拉帕米可抑制细胞内结核分枝杆菌的生长和耐受性，这表明其具有缩短治疗疗程的潜力。去甲维拉帕米、R-维拉帕米以及其他可能的衍生物是有吸引力的替代物，可能具有更好的耐受性。
