Mitini-Nkhoma Steven C, Fernando Narmada, Ishaka G K D, Handunnetti Shiroma M, Pathirana Sisira L
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, No: 90, Cumaratunga Munidasa Mawatha, Colombo 3, Sri Lanka.
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, P.O. Box 30096, Chichiri, Blantyre 3, Malawi.
Tuberc Res Treat. 2020 Nov 20;2020:3767915. doi: 10.1155/2020/3767915. eCollection 2020.
There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide (HCTZ), metformin, omeprazole, pantoprazole, phenytoin, verapamil, and drug X and Y on the growth of free and intracellular BCG. Free and intracellular BCG were cultured in the presence or absence of the test drugs for 3 to 9 days and then quantified. For both free and intracellular bacteria, cultures that were exposed to furosemide, phenytoin, or drug Y yielded lower bacteria counts compared to drug-free controls ( < 0.05). The same was observed with diazoxide, HCTZ, verapamil, and drug X, but only for intracellular BCG ( < 0.05). To assess the effects of the drugs on bactericidal activity of rifampicin, free and intracellular BCG were treated with rifampicin alone or in combination with each of the thirteen test drugs for 3 to 9 days. For extracellular bacteria, higher bacteria clearance rates were observed in cultures exposed to rifampicin in combination with amiloride HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, drug X, or drug Y than those exposed to rifampicin alone, indicating that rifampicin had a synergistic effect with these test drugs. Rifampicin was also synergistic with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, omeprazole, pantoprazole, phenytoin, verapamil, and drug X against intracellular BCG. The antimycobacterial properties exhibited by the ion transport modulators in this study make them viable candidates as adjuncts to the current anti-TB regimens.
迫切需要更好、更安全的结核病（TB）治疗干预措施。我们评估了美国食品药品监督管理局（FDA）批准的离子转运调节剂，即盐酸氨溴索、盐酸阿米洛利、二氮嗪、地高辛、呋塞米、氢氯噻嗪（HCTZ）、二甲双胍、奥美拉唑、泮托拉唑、苯妥英、维拉帕米以及药物X和Y对游离和细胞内卡介苗生长的影响。将游离和细胞内卡介苗在有或无受试药物的情况下培养3至9天，然后进行定量。对于游离和细胞内细菌，与无药物对照组相比，暴露于呋塞米、苯妥英或药物Y的培养物中细菌数量更低（P<0.05）。二氮嗪、HCTZ、维拉帕米和药物X也观察到了同样的情况，但仅针对细胞内卡介苗（P<0.05）。为了评估这些药物对利福平杀菌活性的影响，将游离和细胞内卡介苗单独用利福平或与13种受试药物中的每一种联合处理3至9天。对于细胞外细菌，与单独暴露于利福平的培养物相比，暴露于利福平与盐酸阿米洛利、二氮嗪、地高辛、呋塞米、HCTZ、二甲双胍、泮托拉唑、苯妥英、药物X或药物Y联合的培养物中观察到更高的细菌清除率，这表明利福平与这些受试药物具有协同作用。利福平与盐酸氨溴索、二氮嗪、地高辛、呋塞米、HCTZ、奥美拉唑、泮托拉唑、苯妥英、维拉帕米和药物X联合使用时对细胞内卡介苗也具有协同作用。本研究中离子转运调节剂所表现出的抗分枝杆菌特性使其成为当前抗结核治疗方案辅助药物的可行候选者。
