FabI Inhibitors as Potent, Gut Microbiome-Sparing Antibiotics

项目总结/摘要 革兰氏阴性菌感染对常用抗生素耐药的百分比以1.5%的速度增加。 在过去的十年里，抗生素的发展速度令人震惊，现在迫切需要发现新的抗生素 有效对抗多重耐药革兰氏阴性病原体。我们在理解 革兰氏阴性菌中理化性状与化合物积累之间的关系， 我们将几种仅具有革兰氏阳性活性的抗生素转化为具有抗关键活性的抗生素， 革兰氏阴性病原体。最先进的是我们的FabI抑制剂Fabimycin; FabI抑制是一种新的策略 没有经过批准的抗生素可以达到这个目标。FabI酶的性质是，它仅在 某些致病菌，其中主要是E. coli、克雷伯氏菌（K. pneumoniae和A.鲍曼不动杆菌;法比霉素 对这些病原体大量临床分离物有效，但对有益的 肠道内的细菌。一种革兰氏阴性的活性抗生素， 没有先例，这将是一个非常重要的发展，因为有充分的证据表明， 广谱抗生素导致肠道生态失调。此外，我们的法比霉素的X射线结构结合到 FabI揭示了配体和蛋白质骨架之间的关键相互作用，使细菌的耐药性大大增强。 比单独与氨基酸侧链相互作用更具挑战性。事实上，法比霉素具有 抗性频率低，并且细胞培养中的抗性仅在很长一段时间内演变。令人兴奋的是， 法比霉素在多种小鼠和大鼠感染模型，包括软组织感染模型， 肺炎败血症和尿路感染要成为真正的临床候选药物，法比霉素的治疗指数（TI）需要 要扩大。在此，我们建议通过应用一种新的抗生素来开发更有效的法比霉素。 最近的理解之间的关系，化合物流出和结构，已经出现了从我们的 laboratories.将这些经验应用于法比霉素将使我们能够系统地减少其外排倾向， 导致优化的衍生物的MIC值比法比霉素强5倍， 适当的TI以促进发展。我们已经组建了一个专家团队，拥有所需的全套工具 这项工作：药物化学，了解外排，获得大量的临床分离株， 在小鼠和大鼠中的抗菌功效的复杂模型，以及详细的药代动力学和毒理学 在小鼠、大鼠和狗中进行的研究，以及在小鼠和狗中进行的微生物组研究。我们的关键路径提供了具体的标准 我们遵循抗生素药物开发的最佳实践， 被FDA。我们的计划是在第二年年底前选出主要候选人，然后在剩下的三年里 多年来建立了一个复杂的数据包，将有助于这种抗生素快速转化为临床。

PROJECT SUMMARY/ABSTRACT The percent of Gram-negative bacterial infections that are resistant to common antibiotics has increased at an alarming rate over the last decade, and there is now an acute need for the discovery of novel antibiotics effective against multidrug-resistant Gram-negative pathogens. We have made progress understanding the relationship between physicochemical traits and compound accumulation in Gram-negative bacteria, enabling us to convert several antibiotics with Gram-positive-only activity into versions that possess activity against key Gram-negative pathogens. Most advanced is our FabI inhibitor fabimycin; FabI inhibition is a novel strategy with no approved antibiotics that hit this target. The nature of the FabI enzyme is that it is only essential in certain pathogenic bacteria, chief among them E. coli, K. pneumoniae, and A. baumannii; thus while fabimycin is effective against large clinical isolate panels of these pathogens, it has no activity against beneficial commensal bacteria that reside in the gut. A Gram-negative active antibiotic that spared the gut microbiome is without precedent and would be a very significant development, given the well-documented deleterious effects of broad-spectrum antibiotics in causing gut dysbiosis. In addition, our X-ray structures of fabimycin bound to FabI reveal critical interactions between the ligand and the protein backbone, making bacterial resistance much more challenging to arise than if interactions were solely with amino acid sidechains. Indeed, fabimycin has a low frequency of resistance, and resistance in cell culture only evolves over a long period of time. Excitingly, fabimycin is also active in multiple mouse and rat infection models, including those of soft tissue infection, pneumonia, sepsis, and UTI. To become a true clinical candidate the Therapeutic Index (TI) of fabimycin needs to be widened. Herein we propose development of more potent versions of fabimycin through application of a recent understanding of the relationship between compound efflux and structure that has emerged from our laboratories. Applying these lessons to fabimycin will enable us to systematically reduce its efflux liability, leading to MIC values for optimized derivatives that are 5-fold more potent than fabimycin and will thus have the appropriate TI for advancement. We have assembled a team of experts with the full suite of tools needed for this work: medicinal chemistry, understanding of efflux, access to large panels of clinical isolates, sophisticated models of antibacterial efficacy in mice and rats, and detailed pharmacokinetics and toxicology in mice, rats, and dogs, and microbiome studies in mice and dogs. Our Critical Path provides specific criteria for compound advancement and we are guided by best practices for antibiotic drug development as deliniated by the FDA. Our plan is to select the lead candidate by the end of Year 2, and then spend the remaining three years building a sophisticated data package that will facilitate rapid translation of this antibiotic to the clinic.