Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus
Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus
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DOI：
10.1128/aac.01696-17
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发表时间：
2018-05-01
影响因子：
4.9
通讯作者：
Rohde, Kyle H.
中科院分区：
文献类型：
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作者：
Gupta, Rashmi;Felix, Carolina Rodrigues;Rohde, Kyle H.
结核分枝杆菌和生长迅速的脓肿分枝杆菌是两种重要的人类病原体，可引起难以治愈且需要长时间治疗的持续性肺部感染。耐药结核分枝杆菌菌株的出现和脓肿分枝杆菌的高水平内在耐药性要求新的药物支架有效靶向这两种病原体。在这项研究中，我们评估了他（吡咯烷-亚胺）金（III）大环和螯合物的活性，这些大环和螯合物最初被设计为DNA插入物，能够靶向人类I型和II型拓扑异构酶（Topo1和Topo2），对抗脓肿分枝杆菌和结核分枝杆菌。在体外复制条件下，共鉴定出5种对两种分枝杆菌病原体均有活性的非细胞毒性化合物。我们选择了其中的一个，化合物14，因为它具有有效的抑菌模式和可扩展的合成。该化合物的临床相关性通过其抑制多种结核分枝杆菌和脓肿分枝杆菌临床分离株的能力得到证明。根据先前的数据表明，化合物14可能靶向拓扑异构酶/回转酶，我们证明它与靶向结核分枝杆菌回转酶的氟喹诺酮类药物缺乏交叉耐药。体外酶分析证实了化合物14对细菌拓扑异构酶1A （Topo1）酶的有效活性，但对回转酶没有作用。新型支架，如化合物14，对结核分枝杆菌和脓肿分枝杆菌具有有效的选择性杀菌活性，作用于已验证但未充分开发的靶点，如Topo1，为开发治疗致病性分枝杆菌感染的新疗法提供了一个有希望的起点。
Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis. We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoro-quinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.