Department of Microbiology and Immunology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
Antimicrob Agents Chemother. 2011 Aug;55(8):3861-9. doi: 10.1128/AAC.00474-11. Epub 2011 May 16.
Therapeutic options for tuberculosis (TB) are limited and notoriously ineffective despite the wide variety of potent antibiotics available for treating other bacterial infections. We investigated an approach that enables an expansion of TB therapeutic strategies by using synergistic combinations of drugs. To achieve this, we devised a high-throughput synergy screen (HTSS) of chemical libraries having known pharmaceutical properties, including thousands that are clinically approved. Spectinomycin was used to test the concept that clinically available antibiotics with limited efficacy against Mycobacterium tuberculosis might be used for TB treatment when coadministered with a synergistic partner compound used as a sensitizer. Screens using Mycobacterium smegmatis revealed many compounds in our libraries that acted synergistically with spectinomycin. Among them, several families of antimicrobial compounds, including macrolides and azoles, were also synergistic against M. tuberculosis in vitro and in a macrophage model of M. tuberculosis infection. Strikingly, each sensitizer identified for synergy with spectinomycin uniquely enhanced the activities of other clinically used antibiotics, revealing a remarkable number of unexplored synergistic drug combinations. HTSS also revealed a novel activity for bromperidol, a butyrophenone used as an antipsychotic drug, which was discovered to be bactericidal and greatly enhanced the activities of several antibiotics and drug combinations against M. tuberculosis. Our results suggest that many compounds in the currently available pharmacopoeia could be readily mobilized for TB treatment, including disease caused by multi- and extensively drug-resistant strains for which there are no effective therapies.
尽管有许多强效抗生素可用于治疗其他细菌感染，但结核病 (TB) 的治疗选择仍然有限，而且效果不佳。我们研究了一种方法，通过使用药物协同组合来扩大结核病治疗策略。为了实现这一目标，我们设计了一种针对具有已知药物特性的化学文库的高通量协同筛选 (HTSS)，其中包括数千种临床批准的药物。我们使用大观霉素来测试这一概念，即对于结核分枝杆菌疗效有限的临床可用抗生素，当与协同作用的伙伴化合物联合使用作为增敏剂时，可能用于结核病治疗。使用耻垢分枝杆菌进行的筛选揭示了我们文库中的许多化合物与大观霉素协同作用。其中，包括大环内酯类和唑类在内的几类抗菌化合物，在体外和分枝杆菌感染的巨噬细胞模型中也对结核分枝杆菌具有协同作用。引人注目的是，每种与大观霉素协同作用的增敏剂都独特地增强了其他临床使用抗生素的活性，揭示了许多未被探索的协同药物组合。HTSS 还揭示了一种新型的溴哌利多的活性，溴哌利多是一种用作抗精神病药物的丁酰苯，被发现具有杀菌作用，并大大增强了几种抗生素和药物组合对结核分枝杆菌的活性。我们的研究结果表明，目前药理学中许多化合物可以很容易地用于结核病治疗，包括多药和广泛耐药菌株引起的疾病，这些疾病目前没有有效的治疗方法。
