Discovery of inhibitors of the lipopolysaccharide synthesis pathway enzymes LpxA

脂多糖合成途径酶 LpxA 抑制剂的发现

• 批准号: 7912694
• 负责人: Vicki Nienaber
• 金额: $ 45.63万
• 依托单位: ZENOBIA THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-05 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912694
• 关键词: Acinetobacter baumannii; Active Sites; Address; Affect; Affinity; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antiviral Agents; Bacteria; Bacterial Antibiotic Resistance; Bacterial Genome; Binding; Biochemical; Biological Assay; Cell Wall; Cells; Chemicals; Chlamydia trachomatis; Clinical; Collection; Crystallization; Data; Development; Disabled Persons; Disease; Dose; Drug Kinetics; Endotoxins; Engineering; Enzymes; Epidemiology; Equilibrium; Escherichia coli; Essential Genes; Failure; Funding; Genes; Genomics; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Growth; HIV; Helicobacter pylori; Hydrogen Bonding; Infection; Infection Control; Klebsiella pneumonia bacterium; Lead; Libraries; Ligands; Link; Lipopolysaccharides; Literature; Location; Longevity; Medical; Membrane; Methods; Molecular Weight; Monitor; Mono-S; Organism; Output; Pathway interactions; Patient Care; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Preclinical Drug Evaluation; Property; Proteins; Pseudomonas; Pseudomonas aeruginosa; Reporting; Research; Resistance; Resistance development; Resolution; Scientific Advances and Accomplishments; Screening procedure; Series; Site; Specificity; Structure; Surface Plasmon Resonance; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Viral; X-Ray Crystallography; Xenobiotics; assay development; base; chemical property; combat; computerized tools; design; drug discovery; enzyme pathway; handicapping condition; high throughput screening; improved; inhibitor/antagonist; lead series; novel; novel strategies; novel therapeutics; pathogen; phase 1 study; preference; programs; protein complex; public health relevance; resistance mechanism; structural biology; success; three dimensional structure; tool; urinary gonadotropin fragment

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.

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不断取得科学进步，以克服当时的临床问题。解决耐药机制的一种方法是从许多不同的方面攻击细菌，就像在艾滋病毒抗病毒领域所做的那样。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，并且在新疗法的发现方面几乎没有取得进展。即使在基因组学时代到来之后，完整的细菌基因组已被测序并确定了独特的酶途径。通过高通量筛选方法筛选了多种靶点，但没有效果。最近，对这种高失败率的原因进行了分析，得出的结论是，为适应所有疾病适应症而设计的传统 HTS 文库不具备抗菌药物所需的特性。回顾性分析表明，一般来说，成功的抗菌剂比其他药物分子极性更大、更大，事实上，不符合构建大多数大型 HTS 库的标准。在本提案中，我们将使用另一种方法，即基于片段的先导物发现，而不是为抗菌研究重建 HTS 库，这将是一项艰巨且昂贵的任务，其中筛选药物片段而不是完整分子。由于化合物较小，因此库不需要很大或组装成本不高。此外，当我们发现与我们的靶标结合并开始增加片段大小的化合物时，我们可以在增强效力的同时设计抗生素友好的化学特性。我们专注于革兰氏阴性细菌的细菌细胞壁合成途径，针对两种蛋白质：LpxA 和 LpxD。这两种蛋白质都是必需的，并且由于细胞壁可以引起对某些抗生素的耐药性，因此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演变的问题，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不断取得科学进步，以克服当时的临床问题。我们正在通过寻找革兰氏阴性细菌中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化合物发现方法，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识别抗菌化合物方面基本上不成功，主要是因为我们一直在错误的地方（在化学空间中）寻找。成功抗生素的化学特性已被确定，并将在整个研究过程中得到遵守。