Discovery of inhibitors of the lipopolysaccharide synthesis pathway enzymes LpxA

描述（由申请人提供）：自抗生素时代开始以来，细菌对抗生素的耐药性一直是一个不断发展的问题，需要多年来在抗生素发现、流行病学监测和感染控制技术方面取得一致的科学进展，以克服当时的临床问题。解决耐药机制的一种方法是在许多不同的战线上攻击细菌，就像在抗病毒领域对HIV所做的那样。然而，与抗病毒领域不同的是，大多数商业抗生素是多年前发现的，在发现新疗法方面几乎没有进展。这甚至是在基因组学时代的黎明之后，当时完整的细菌基因组被测序，独特的酶途径被鉴定。大量的目标已被筛选的高通量筛选方法是徒劳的。最近，已经分析了这种高失败率的原因，并得出结论，传统的HTS库，旨在适应所有疾病的适应症，不具备抗菌剂所需的属性。回顾性分析表明，一般来说，成功的抗菌剂比其他药物分子更极性和更大，事实上，不符合用于建立大多数大型HTS收集的标准。在这项提议中，我们将使用另一种方法，基于片段的先导发现，而不是重建HTS库用于抗菌研究，这将是一项巨大而昂贵的工作，其中筛选药物片段而不是完整的分子。因为化合物更小，所以库不需要很大或组装成本很高。此外，当我们发现与我们的目标结合的化合物并开始增加片段的大小时，我们可以在建立效力的同时设计对有害生物友好的化学性质。我们专注于革兰氏阴性菌中的细菌细胞壁合成途径，靶向两种蛋白质：LpxA和LpxD。这两种蛋白质都是必不可少的，因为细胞壁可以引起对某些抗生素的耐药性，抑制剂不仅可以作为单一疗法的治疗剂，而且可以与现有的耐药抗生素共同给药。 公共卫生相关性：自抗生素时代开始以来，细菌对抗生素的耐药性一直是一个不断发展的问题，需要多年来在抗生素发现、流行病学监测和感染控制技术方面取得一致的科学进展，以克服当时的临床问题。我们通过在革兰氏阴性菌中寻找细菌细胞壁合成的抑制剂来解决耐药机制。我们使用基于片段的先导发现方法针对该途径中的两种蛋白质：LpxA和LpxD。传统的现代药物发现方法在鉴定抗菌化合物方面基本上是不成功的，主要是因为我们一直在错误的地方（化学空间）寻找。成功抗生素的化学性质已经确定，并将在本研究过程中坚持。

DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics has been an evolving problem since the dawn of the antibiotics era, requiring consistent scientific advances over the years in antibiotic discovery, epidemiological surveillance and infection control techniques to overcome the then-current clinical problem. One way to address resistance mechanisms is to attack the bacteria on many different fronts as has been done in the anti-viral field with HIV. However, unlike in the antiviral field, most commercial antibiotics were discovered many years ago and little advancement has been made in the discovery of novel therapeutics. This is even after the dawn of the genomics era when complete bacterial genomes were sequenced and unique enzymatic pathways identified. A multitude of targets have been screened by high-throughput screening methods to no avail. Recently, the reason for this high failure rate has been analyzed and conclusions drawn that traditional HTS libraries, designed to fit all disease indications, do not possess the properties required for anti-bacterial agents. Retrospective analysis reveal that in general successful antibacterial agents are more polar and larger than other drug molecules, and in fact, do not fit the criteria used to build most large HTS collections. Rather than re-building HTS libraries for antibacterial research which would be a tremendous and costly undertaking, in this proposal, we will use another method, fragment-based lead discovery, where fragments of drugs are screened rather than intact molecules. Because the compounds are smaller, the libraries need not be large or costly to assemble. Furthermore, as we find compounds that bind to our target and begin to increase the size of the fragments, we can design in antibiotic-friendly chemical properties at the same time we are building in potency. We are focusing on the bacterial cell wall synthesis pathway in gram negative bacteria, targeting two proteins: LpxA and LpxD. Both proteins are essential and because the cell wall can invoke resistance to some antibiotics, inhibitors may not only be therapeutic agents as a mono-therapy but could be co-dosed with existing resistant antibiotics. PUBLIC HEALTH RELEVANCE: Bacterial resistance to antibiotics has been an evolving problem since the dawn of the antibiotics era, requiring consistent scientific advances over the years in antibiotic discovery, epidemiological surveillance and infection control techniques to overcome the then-current clinical problem. We are addressing resistance mechanisms by finding inhibitors of bacterial cell wall synthesis in gram negative bacteria. We are targeting two proteins in the pathway: LpxA and LpxD using the method of fragment- based lead discovery. Traditional modern drug discovery methods have been largely unsuccessful in identifying antibacterial compounds primarily because we have been looking in the wrong place (in chemical space). Chemical properties of successful antibiotics have been identified and will be adhered to through the course of this study.