FabI Inhibitors as Potent, Gut Microbiome-Sparing Antibiotics

项目摘要/摘要 对常见抗生素耐药的革兰氏阴性细菌感染的百分比以 过去十年的惊人速度，现在迫切需要发现新的抗生素 对耐多药的革兰氏阴性病原体有效。我们已经取得了进展，理解 革兰氏阴性杆菌理化性状与化合物积累的关系 美国将把几种仅具有革兰氏阳性活性的抗生素转换为具有抗KEY活性的版本 革兰氏阴性病原体。最先进的是我们的Fabi抑制剂法比霉素；Fabi抑制是一种新的策略 没有获得批准的抗生素达到这一目标。Fabi酶的本质是它只在 某些致病菌，主要是大肠埃希菌、肺炎克雷伯氏菌和鲍曼不动杆菌；因此，法比霉素 对这些病原体的大型临床分离群有效，但对有益的 寄生在肠道中的共生细菌。一种可以避免肠道微生物群的革兰氏阴性活性抗生素是 没有先例，考虑到有据可查的有害影响，这将是一个非常重要的发展 导致肠道生物失调的广谱抗生素。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 与仅与氨基酸侧链相互作用相比，更具挑战性。事实上，法比霉素有一种 耐药频率低，细胞培养中的抗药性只会在很长一段时间内进化。令人兴奋的是， 法比霉素在多种小鼠和大鼠感染模型中也是有效的，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 需要加宽。在此，我们建议开发更有效的法比霉素版本，通过应用一种 最近对复合外流和结构之间的关系的理解已经从我们的 实验室。将这些经验教训应用于法比霉素将使我们能够系统地减少其外排风险， 导致优化的衍生物的MIC值是法比霉素的5倍，因此将具有 适合晋升的TI。我们已经组建了一支专家团队，配备了所需的全套工具 对于这项工作：药物化学，对外排的理解，获得临床分离株的大面板， 小鼠和大鼠抗菌效果的复杂模型，以及详细的药代动力学和毒理学 在小鼠、大鼠和狗身上，以及在小鼠和狗身上进行微生物组研究。我们的关键路径提供了具体的标准 对于化合物的进展，我们遵循抗生素药物开发的最佳实践 被美国食品和药物管理局。我们的计划是在第二年年底选出主要候选人，然后用剩下的三年时间 多年来建立了一个复杂的数据包，将促进这种抗生素的快速转换到临床。

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.