Development of FosA Inhibitors to Potentiate Fosfomycin Activity in Gram-Negative Pathogens

开发 FosA 抑制剂以增强磷霉素对革兰氏阴性病原体的活性

• 批准号: 10545935
• 负责人: Jay Edward Wrobel
• 金额: $ 30.65万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545935
• 关键词: Abdominal Infection; Acute; Adjuvant; Affinity; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteremia; Bacteria; Bacterial Infections; Bacterial Pneumonia; Binding; Biological; Biological Assay; Carbon; Chemicals; Clinical; Crystallization; Data; Development; Drug Industry; Drug Kinetics; Drug Targeting; Drug resistance; Ensure; Enterobacter; Epoxy Compounds; Escherichia coli; Evaluation; Excretory function; Formulation; Fosfomycin; Foxes; Future; Genes; Glutathione; Glutathione S-Transferase; Goals; Gram-Negative Bacteria; Homologous Gene; Hospitals; Human; Industry Standard; Infection; Intra-abdominal; Intravenous; Klebsiella pneumoniae; Legal patent; Lung infections; Measures; Mediating; Metabolism; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Oral; Pathway interactions; Penetration; Pharmaceutical Chemistry; Phase; Pneumonia; Predisposition; Process; Production; Property; Proteins; Pseudomonas aeruginosa; Public Health; Records; Research; Resistance; Resistance development; Roentgen Rays; Route; Safety; Scientist; Small Business Technology Transfer Research; Structure; Therapeutic Uses; Toxic effect; Transferase; Universities; Urinary tract infection; Ventilator; absorption; analog; antimicrobial; base; clinically relevant; combat; design; dimer; drug development; drug discovery; experience; in vitro Assay; in vitro activity; inhibitor; insight; iterative design; lead optimization; novel; novel strategies; nucleophilic addition; pathogen; pharmacophore; pre-clinical; resistant strain; scale up; small molecule inhibitor; success

Summary. Antimicrobial resistance is widely recognized as one of the most significant public health threats of the century. Many bacterial infections have become difficult to treat due to antimicrobial resistance, and there is an urgent need to develop new strategies to combat these resistant pathogens. One such strategy is to reposition older antibiotics that have long-track records of safety in human. Fosfomycin (FOM) is an etablished antibiotic which inactivates UDP-N-acetylglucosamine enolpyruvyl transferase in both Gram-positive and -negative pathogens. Currently, FOM is exclusively used as an oral formulation for the treatment of urinary tract infections given its excellent activity against Escherichia coli. However, an intravenous FOM formulation is used elsewhere, and is currently pending FDA approval in U.S. Furthermore, an ongoing NIAID-sponsored trial (NCT03910673) is exploring whether intravenous FOM can effectively treat lung infections, such as hospital-acquired and ventilator-associated bacterial pneumonia. FosA is a dimeric K+- and Mn2+-dependent glutathione S-transferase that catalyzes the nucleophilic addition of glutathione to carbon-1 in the epoxide ring of FOM, rendering the antibiotic inactive. E. coli lacks intrinsic chromosomal fosA, thus explaining its acute susceptibility to FOM. However, fosA homologues are chromosomally encoded by many Gram-negative species including Pseudomonas aeruginosa and Klebsiella pneumoniae. Our prior research has clearly demonstrated that this intrinsic production of FosA confers FOM resistance, and that inactivation of FosA provides a novel approach to increase the sensitivity of carbepenem resistant Gram-negative pathogens to FOM, thus highlighting a novel pathway to expand the use of FOM to a wide range of Gram-negative species. Importantly, and central to this application, we recently identified and patented a first-in-class, competitive small molecule inhibitor of FosA (ANY1) which potentiates FOM activity against Gram-negative pathogens that harbor the fosA gene. Using insights from the ANY1-FosA X-ray crystal structure, we have designed and prepared an analog that has ~10X greater potency, showing that further SAR development is possible. The aims in this proposal are (1) medicinal chemistry optimization of FosA inhibitors, (2) evaluation and optimization of ADME properties, and (3) biological evaluation against a broad panel of XDR Gram-negative clinical isolates. We anticipate that such a combination could be used to treat invasive infections including bacteremia, pneumonia, intra-abdominal infections and complicated UTIs caused by Gram-negative bacteria that harbor fosA (e.g., K. pneumoniae, Enterobacter spp., P. aeruginosa), including extremely drug resistant strains. In this Phase I proposal, we will identify and evaluate FosA inhibitors based on ANY1 by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience of the Sluis-Cremer lab at the University of Pittsburg in the experimental aspects of FosA inhibition and antibiotic therapy.

概括。抗菌抗性被广泛认为是最重要的公共卫生威胁之一 世纪。由于抗菌素耐药性，许多细菌感染变得难以治疗，并且有 迫切需要制定新的策略来对抗这些抗性病原体。一种这样的策略是重新定位 具有长期安全记录的人类安全记录的较旧抗生素。 Fosfomycin（FOM）是一种固定的抗生素 这会使革兰氏阳性和阴性的UDP-N-乙酰葡萄糖乙酰葡萄糖转移酶均活化 病原体。目前，FOM专门用作治疗尿路感染的口服配方 鉴于其对大肠杆菌的出色活动。但是，静脉注射FOM公式在其他地方使用 目前，正在进行的NIAID赞助试验（NCT03910673）等待美国FDA批准。 正在探索静脉注射FOM是否可以有效治疗肺部感染，例如医院的经验和 呼吸机相关的细菌性肺炎。 FOSA是二聚体K+ - 和MN2+依赖性谷胱甘肽S-转移酶 这催化了在FOM环氧化环中将谷胱甘肽添加到碳-1中的亲核添加，从而使 抗生素无活性。大肠杆菌缺乏固有的染色体FOSA，因此解释了其对FOM的急性敏感性。 然而，FOSA同源物是许多革兰氏阴性物种编码的染色体 铜绿假单胞菌和肺炎克雷伯氏菌。我们先前的研究清楚地表明了这一点 FOSA的内在产生赋予FOM抵抗力，而FOSA的失活为一种新颖的方法提供了一种新颖的方法 提高抗p肾上腺革兰氏阴性病原体对FOM的敏感性，从而突出显示一种新颖 将FOM扩展到各种革兰氏阴性物种的途径。重要的是，这是核心 应用，我们最近确定并为FOSA的第一类竞争性小分子抑制剂提供了专利 （Any1）增强了含有FOSA基因的革兰氏阴性病原体的FOM活性。使用 从Any1-Fosa X射线晶体结构中的见解，我们设计并制备了一个约为10倍的类似物 更大的效力，表明进一步的SAR开发是可能的。该提案的目的是（1）药用 FOSA抑制剂的化学优化，（2）评估和优化ADME性质，（3）生物学 对XDR革兰氏阴性临床分离株的广泛面板的评估。我们预计这样的组合 可用于治疗包括菌血症，肺炎，腹腔内感染和 由革兰氏阴性细菌引起的复杂尿道（例如，肺炎K.肺炎，肠杆菌属， 铜绿假单胞菌），包括极其耐药菌株。在此阶段我的建议中，我们将识别和评估 FOSA抑制剂基于Any1，通过结合了药物和药物化学专业知识 Fox Chase化学多样性中心（FCCDC）的科学家具有专业知识和经验 匹兹堡大学的Sluis-Cremer Lab在FOSA抑制和抗生素的实验方面 治疗。