The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance.
The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance.
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人质子泵抑制剂抑制结核分枝杆菌利福平外排和巨噬细胞诱导的利福平耐受。
DOI：
10.1073/pnas.2215512120
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发表时间：
2023-02-14
影响因子：
11.1
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
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作者：
Lake MA;Adams KN;Nie F;Fowler E;Verma AK;Dei S;Teodori E;Sherman DR;Edelstein PH;Spring DR;Troll M;Ramakrishnan L
结核病需要长期治疗，因为结核分枝杆菌产生了抗菌素耐受性。当分枝杆菌感染巨噬细胞时，耐受性早期发展，并且归因于巨噬细胞驻留时细菌药物外排泵的诱导。在这里，我们表明，药物耐受性是由于质子梯度依赖性结核分枝杆菌外排泵被维拉帕米和其他P-糖蛋白抑制剂，包括质子泵抑制剂抑制。我们的工作为未来的药物发现和质子泵抑制剂或其类似物的开发提供了一个简单的平台，具有潜在的抗结核治疗缩短潜力。结核病治疗需要长达数月的多种药物联合化疗，治疗时间较短会导致复发。缩短治疗的一个主要障碍是结核分枝杆菌在感染后早期和感染巨噬细胞后几天内对所施用的药物产生耐受性。多条证据表明巨噬细胞诱导的药物耐受是由分枝杆菌药物外排泵介导的。在这里，使用测定直接测量药物外排，我们发现，M。结核病通过质子梯度依赖性机制转运一线抗结核药物利福平。我们发现，维拉帕米，一种已知的外排泵抑制剂，抑制巨噬细胞诱导的利福平耐受，也抑制结核分枝杆菌利福平外排。与巨噬细胞诱导的耐受一样，维拉帕米的钙通道抑制特性并不是其抑制利福平流出所必需的。通过测试维拉帕米类似物，我们发现维拉帕米直接抑制M。结核病药物外排通过其人类P-糖蛋白（PGP）样抑制活性泵出。筛选出具有PGP偶联抑制活性的常用药物，发现有许多抑制利福平外排的药物，包括质子泵抑制剂（PPI）如奥美拉唑。与维拉帕米一样，PPI抑制巨噬细胞诱导的利福平耐受以及巨噬细胞内生长，这也与分枝杆菌外排泵活性有关。我们的检测方法为M.结核外排泵抑制剂，抑制体内药物耐受性和生长。
Tuberculosis requires long-term treatment because of the development of antimicrobial tolerance by Mycobacterium tuberculosis. Tolerance develops early when mycobacteria infect macrophages and has been attributed to the induction of bacterial drug efflux pumps upon macrophage residence. Here, we show that drug tolerance is due to proton gradient-dependent M. tuberculosis efflux pumps that are inhibited by verapamil and other P-glycoprotein inhibitors, including proton pump inhibitors. Our work develops a facile platform for future drug discovery and for the development of proton pump inhibitors or their analogs with potential anti-TB treatment shortening potential. Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that Mycobacterium tuberculosis becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that M. tuberculosis transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits M.tuberculosis rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits M. tuberculosis drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for M. tuberculosis efflux pump inhibitors that inhibit in vivo drug tolerance and growth.
DOI：
10.1093/ndt/gfw349
发表时间：
2017-04-01
期刊：
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
影响因子：
--
作者：
Tomlinson LA;Fogarty DG;Douglas I;Nitsch D
通讯作者：
Nitsch D