Structure and property driven optimization of fatty acid synthesis inhibitors for

脂肪酸合成抑制剂的结构和性能驱动优化

基本信息

批准号：
8771453
负责人：
Frederick Cohen
金额：
$ 40.71万
依托单位：
ACHAOGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771453
关键词：
Acetyl Coenzyme A Achievement Affect Affinity Anti-Bacterial Agents Antibiotics Back Bacteria Bacterial Antibiotic Resistance Binding Biological Assay Biotin carboxylase Carbonates Cell Death Cell surface Cells Chemicals Chemistry Clinical Clinical Trials Collaborations Computing Methodologies Country Cytoplasm Data Detection Development Endotoxins Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Escherichia coli Fatty Acids Feeds Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Gram-Positive Bacteria Health Homologous Gene Human Infection Ions Klebsiella pneumonia bacterium Knock-out Knowledge Ligand Binding Lipids Lipopolysaccharides Literature Malonyl Coenzyme A Measures Medical Membrane Methods Microbiology Molecular Models Multi-Drug Resistance Multienzyme Complexes Organic Chemistry Organism Outcome Pathway interactions Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Property Pseudomonas aeruginosa Public Health Publishing Pump Research Resistance Route Saturated Fatty Acids Series Solutions Solvents Source Structure Testing Time United States Work analog antimicrobial bactericide base combat design drug development drug discovery experience feeding flexibility hydroxy fatty acid improved information gathering inhibitor/antagonist inorganic phosphate long chain fatty acid molecular modeling novel pathogen prevent programs screening vector

项目摘要

DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics has been an evolving problem since the dawn of the antibiotics era. Isolates of Gram-negative bacteria (GNB) exist that are resistant to nearly all approved antibiotics, and these pathogens are rapidly spreading across the country and across the globe. At the same time, the pipeline of new antibiotics is nearly empty. By contrast to Gram-positive bacteria, Gram-negative organisms protect themselves with an additional outer bilayer membrane. The barrier function of this outer membrane relies on lipopolysaccharide (LPS, or endotoxin), the predominant lipid moiety on the cell surface. Agents that inhibit the synthesis of LPS, such as inhibitors of the enzyme LpxC, are rapidly bactericidal. Indeed, Achaogen has developed an LpxC inhibitor, ACHN-975, that was the first agent in its class to enter Phase I clinical trials. The research program that led to the advancement of ACHN-975 into clinical trials started with a known LpxC inhibitor, CHIR-090. Achaogen then used our deep knowledge of medicinal chemistry rules for synthesizing agents that cross both Gram-negative membranes, and our extensive microbiology capabilities to design, synthesize and test new analogs with improved activity. To further exploit the LPS synthesis pathway, we are examining the enzyme AccC otherwise known as biotin carboxylase. This enzyme catalyzes an early step in Type-II fatty-acid synthesis. Gram-negative bacteria require this enzyme to synthesize the ?-hydroxy lipids that are unique to LPS. As there are no environmental sources of ?-hydroxy fatty acids (by contrast to saturated fatty acids), inhibition of AccC will result in rapid cell death. Inhibitors of purified AccC from Gram-negative bacteria have been published in the literature, and the binding mode of these compounds to the enzyme is well understood through a large number of publicly available co-crystal structures. However, these leads are only weakly active against pathogenic GNB. We believe that we understand the properties of these compounds that prevent their activity in wild-type GNB. Achaogen will again use our deep understanding of medicinal chemistry in the Gram-negative space and our microbiology capabilities to design, synthesize and test new AccC inhibitors with improved properties that will be more active against pathogenic GNB. The successful outcome of this project will be a series of drug-like molecules that are potent inhibitors of purified AccC and have antimicrobial activity against wild-type GNB with MIC's in the range of ≤ 0.5 ug/mL. Achievement of these goals will allow us to initiate a full scale drug development program.

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，革兰氏阴性菌（GNB）分离株对几乎所有批准的抗生素都具有耐药性，并且这些病原体正在迅速传播。与此同时，新抗生素的研发渠道几乎是空的。与革兰氏阳性菌相比，革兰氏阴性菌通过额外的双层膜来保护自己。膜依赖于脂多糖（LPS，或内毒素），抑制 LPS 合成的试剂，例如 LpxC 酶抑制剂，可以快速杀菌。事实上，Achaogen 开发了一种 LpxC 抑制剂 ACHN。 -975，这是同类产品中第一个进入 I 期临床试验的药物。 ACHN-975 的临床试验始于已知的 LpxC 抑制剂 CHIR-090，然后利用我们对合成跨革兰氏阴性膜的药物化学规则的深入了解，以及我们广泛的微生物学能力来设计、合成和生产。测试具有改进活性的新类似物为了进一步开发 LPS 合成途径，我们正在研究 AccC 酶（也称为生物素羧化酶），该酶催化 II 型的早期步骤。革兰氏阴性细菌需要这种酶来合成 LPS 特有的 α-羟基脂质，因为没有 α-羟基酸脂肪酸的环境来源（与饱和脂肪酸相比），因此抑制 AccC。从革兰氏阴性细菌中纯化的 AccC 抑制剂已在文献中发表，并且通过大量公开的共晶结构可以很好地了解这些化合物与酶的结合模式。这些线索只是微弱的我们相信，我们了解这些化合物在野生型 GNB 中的活性，Achaogen 将再次利用我们对革兰氏阴性领域药物化学的深入了解以及我们的微生物学能力来设计、合成和生产。测试具有改进特性的新型 AccC 抑制剂，这些抑制剂对致病性 GNB 更具活性。该项目的成功结果将是一系列药物样分子，它们是纯化 AccC 的有效抑制剂，并对野生型 GNB 具有抗菌活性。 MIC 在 ≤ 0.5 ug/mL 范围内。实现这些目标将使我们能够启动全面的药物开发计划。