Bisacchi Gregory S, Manchester John I
AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
ACS Infect Dis. 2015 Jan 9;1(1):4-41. doi: 10.1021/id500013t. Epub 2014 Dec 23.
The introduction into clinical practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clinical proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I. In this review, we analyze the historical attempts to discover and develop agents within this class and highlight factors that might have hindered those efforts. Within the last 15 years, however, our technical understanding of the molecular details of the inhibition of the gyrase and topo IV ATPases, the factors governing resistance development to such inhibitors, and our knowledge of the physical properties required for robust clinical drug candidates have all matured to the point wherein the industry may now address this mechanism of action with greater confidence. The antibacterial spectrum within this class has recently been extended to begin to include serious Gram negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In spite of this recent technical progress, adverse economics associated with antibacterial R&D over the last 20 years has diminished industry's ability to commit the resources and perseverance needed to bring new-class agents to launch. Consequently, a number of recent efforts in the ATPase class have been derailed by organizational rather than scientific factors. Nevertheless, within this context we discuss the unique opportunity for the development of ATPase inhibitors of gyrase and topo IV as new-class antibacterial agents with broad spectrum potential.
将细菌DNA旋转酶和拓扑异构酶IV（拓扑异构酶IV）的ATP酶抑制剂引入临床实践将代表一种用于治疗耐药细菌感染的新型药物。新生霉素是该类药物中唯一的历史成员，在20世纪50年代后期确立了这种新机制的临床概念验证，但它的使用迅速减少，最终退出市场。尽管整个生物制药行业付出了巨大且持久的努力来开发该类别的其他药物，但新生霉素仍然是唯一一种进入I期以上研究阶段的旋转酶和拓扑异构酶IV的ATP酶抑制剂。在本综述中，我们分析了发现和开发该类别药物的历史尝试，并强调了可能阻碍这些努力的因素。然而，在过去15年中，我们对旋转酶和拓扑异构酶IV的ATP酶抑制的分子细节、对此类抑制剂产生耐药性的控制因素以及对强大临床候选药物所需物理性质的技术理解都已成熟，以至于该行业现在可以更有信心地应对这种作用机制。该类别的抗菌谱最近已扩大，开始包括一些严重的革兰氏阴性病原体，如铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌。尽管最近取得了技术进步，但过去20年中与抗菌药物研发相关的不良经济状况削弱了该行业投入资源和毅力将新型药物推向市场的能力。因此，ATP酶类别最近的一些努力因组织因素而非科学因素而受阻。尽管如此，在此背景下，我们讨论了开发旋转酶和拓扑异构酶IV的ATP酶抑制剂作为具有广谱潜力的新型抗菌药物的独特机会。
