Novel Antibiotics Targeting Respiratory ATP Synthesis in Gram-Positive Pathogenic Bacteria
Novel Antibiotics Targeting Respiratory ATP Synthesis in Gram-Positive Pathogenic Bacteria
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DOI：
10.1128/aac.00273-12
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Koul, Anil
中科院分区：
文献类型：
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作者：
Balemans, Wendy;Vranckx, Luc;Koul, Anil
耐药细菌的出现代表了高的、未满足的医疗需求，并且强烈需要发现作用于新细菌靶标的新抗菌剂。ATP合酶已被证实为结核分枝杆菌中的抗菌靶标，其中其活性可被二芳基喹啉TMC 207特异性阻断。然而，TMC 207的效力仅限于分枝杆菌，对其他革兰氏阳性或革兰氏阴性细菌的生长几乎没有影响。在这里，我们确定了二芳基喹啉类药物对关键革兰氏阳性病原体的活性，显着扩展了二芳基喹啉类药物的抗菌谱。这些化合物抑制生长的金黄色葡萄球菌在休眠状态，以及在代谢休息的细菌生长在生物膜培养。此外，时间杀灭实验表明，选择的命中是快速杀菌。耐药突变被映射到ATP合酶，生化分析以及药物-靶标相互作用研究揭示ATP合酶是这些化合物的靶标。此外，敲低ATP合酶表达强烈抑制S.金黄色葡萄球菌，揭示了该靶标在细菌生长和代谢中的关键作用。我们的数据代表了在关键革兰氏阳性病原体中使用二芳基喹啉类抗菌药物的原理证明。我们的研究结果表明，拓宽这类化学品的抗菌谱是可能的，而不会偏离目标。二芳基喹啉类的开发可能代表了对抗革兰氏阳性病原体的有希望的策略。
Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.