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Targeting bacterial energetics to produce new antimicrobials
Drug Resistance Updates ( IF 24.3 ) Pub Date : 2017-11-02 , DOI: 10.1016/j.drup.2017.11.001
Kiel Hards , Gregory M. Cook

From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted “one-size fits all” approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non-replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory “uncouplers” disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development.



中文翻译:

靶向细菌能量产生新的抗菌素

从抗药性战争到癌症生物学,甚至到农业和环境保护:迫切需要快速有效的解决方案来控制感染和疾病。小分子抑制剂的开发曾经是解决这些各种问题的公认的“千篇一律”的方法,但是持久性和耐药性却可能使社会重返抗生素时代。对于我们大多数与临床相关的抗生素,仅开发了细菌中的五个基本细胞靶标。这些包括:细胞壁合成,细胞膜功能,蛋白质和核酸生物合成以及抗代谢物。现在,这些靶标中的许多靶标由于快速传播的抗菌素耐药性以及靶向非复制性细胞(姊妹子)的需要而受到损害。最近,FDA批准苯达喹啉(BDQ,商品名Sirturo)用于治疗耐多药结核病,这是前所未有的医学突破。BDQ靶向膜结合的F1 F o -ATP合酶,验证了细胞能量生成机制是药物发现的新目标空间。最近,除与酶靶标结合外,BDQ和其他几种FDA批准的药物还被证明是破坏跨膜电化学梯度的呼吸“解偶联剂”。在这篇综述中,我们总结了生物能系统在分枝杆菌持久性中的作用,并讨论了解偶联剂的多目标性质以及这些分子在未来药物开发中的地位。

更新日期:2017-11-02
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