Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India.
J Antimicrob Chemother. 2019 May 1;74(5):1317-1322. doi: 10.1093/jac/dkz018.
Non-tuberculous mycobacteria are emerging pathogens of significant worldwide interest because they have inherent drug resistance to a wide variety of FDA-approved drugs and cause a broad range of serious infections. In order to identify new drugs active against non-tuberculous mycobacteria, we identified disulfiram, utilized for treatment of alcohol dependence, as exhibiting potent growth-inhibitory activity against non-tuberculous mycobacteria.
Whole-cell growth inhibition assays were used to screen and identify novel inhibitors. The hit compounds were tested against Vero cells to determine the selectivity index, and this was followed by determining time-kill kinetics against Mycobacterium fortuitum and Mycobacterium abscessus. Disulfiram's ability to synergize with several approved drugs utilized for the treatment of M. fortuitum and M. abscessus was determined using fractional inhibitory concentration indexes followed by determining its ability to reduce mycobacterial infections ex vivo. Finally, disulfiram's in vivo potential was determined in a neutropenic murine model mimicking mycobacterial infection.
We identified disulfiram as possessing potent antimicrobial activity against non-tuberculous mycobacteria. Disulfiram exhibited concentration- and time-dependent bactericidal activity against M. fortuitum as well as against M. abscessus and synergized with all drugs utilized for their treatment. Additionally, disulfiram reduced bacterial load in macrophages in an intracellular killing assay better than amikacin. When tested in a murine neutropenic M. fortuitum infection model, disulfiram caused significant reduction in bacterial load in kidneys.
Disulfiram exhibits all properties required for it to be repositioned as a novel anti-mycobacterial therapy and possesses a potentially new mechanism of action. Thus, it can be considered as a potent structural lead for the treatment of non-tuberculous mycobacterial infections.
非结核分枝杆菌是一种新兴的病原体，具有广泛的药物固有耐药性，能够引起多种严重感染，引起了全球范围内的广泛关注。为了寻找针对非结核分枝杆菌的新药，我们发现了一种用于治疗酒精依赖的药物——戒酒硫，它对非结核分枝杆菌具有很强的生长抑制活性。
采用全细胞生长抑制试验筛选和鉴定新的抑制剂。对候选化合物进行了 Vero 细胞毒性试验，以确定其选择性指数，然后测定其对偶然分枝杆菌和脓肿分枝杆菌的时间杀伤动力学。通过测定部分抑菌浓度指数，确定了戒酒硫与几种用于治疗偶然分枝杆菌和脓肿分枝杆菌的已批准药物的协同作用，并进一步测定了其降低分枝杆菌感染的能力。最后，通过建立中性粒细胞减少的小鼠模型模拟分枝杆菌感染，测定了戒酒硫的体内潜力。
我们发现戒酒硫对非结核分枝杆菌具有很强的抗菌活性。戒酒硫对偶然分枝杆菌和脓肿分枝杆菌均表现出浓度和时间依赖性杀菌活性，并与所有用于治疗的药物协同作用。此外，在细胞内杀伤试验中，戒酒硫比阿米卡星更能降低巨噬细胞中的细菌载量。在中性粒细胞减少的小鼠偶然分枝杆菌感染模型中，戒酒硫能显著降低肾脏中的细菌负荷。
戒酒硫具有作为新型抗分枝杆菌治疗药物所需的所有特性，并且具有潜在的新作用机制。因此，它可以被认为是治疗非结核分枝杆菌感染的一种有效的结构先导化合物。
