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: 10684118
• 负责人: Jay Edward Wrobel
• 金额: $ 29.16万
• 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/10684118
• 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; Data; Development; Drug Industry; Drug Kinetics; Drug Targeting; Drug resistance; Ensure; Enterobacter; Epoxy Compounds; Escherichia coli; Evaluation; Excretory function; Formulation; Fosfomycin; Future; Genes; Glutathione; Glutathione S-Transferase; Goals; Gram-Negative Bacteria; Homologous Gene; Hospitals; Human; Industry Standard; Infection; Intra-abdominal; Intravenous; Klebsiella pneumoniae; Lead; 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; Positioning Attribute; Predisposition; Process; Production; Property; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; 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; 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 Klebsiella pneumoniae; 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。抗生素耐药性被广泛认为是最重大的公共卫生威胁之一 世纪。许多细菌感染由于抗菌药物耐药性而变得难以治疗，并且 迫切需要制定新策略来对抗这些耐药病原体。其中一项策略是重新定位 具有长期人类安全记录的较旧抗生素。磷霉素 (FOM) 是一种成熟的抗生素 使革兰氏阳性和阴性的 UDP-N-乙酰氨基葡萄糖烯醇丙酮酰转移酶失活 病原体。目前，FOM仅作为口服制剂用于治疗尿路感染 鉴于其对大肠杆菌具有出色的活性。然而，静脉注射 FOM 制剂在其他地方使用， 目前正在美国等待 FDA 批准。此外，NIAID 赞助的一项正在进行的试验 (NCT03910673) 正在探索静脉注射 FOM 是否可以有效治疗肺部感染，例如医院获得性和 呼吸机相关细菌性肺炎。 FosA 是一种二聚体 K+- 和 Mn2+ 依赖性谷胱甘肽 S-转移酶 催化谷胱甘肽与 FOM 环氧化物环中的碳-1 发生亲核加成反应， 抗生素无效。大肠杆菌缺乏内在的染色体 fosA，因此解释了它对 FOM 的急性易感性。 然而，fosA 同源物由许多革兰氏阴性物种在染色体上编码，包括 铜绿假单胞菌和肺炎克雷伯菌。我们之前的研究已经清楚地表明，这 FosA 的内在产生赋予了 FOM 抗性，而 FosA 的失活提供了一种新的方法 增加碳青霉烯耐药革兰氏阴性病原体对 FOM 的敏感性，从而突出了一种新的 将 FOM 的用途扩大到广泛的革兰氏阴性物种的途径。重要的是，也是这一点的核心 申请中，我们最近发现了一种一流的、有竞争力的 FosA 小分子抑制剂并获得了专利 (ANY1)，可增强 FOM 对含有 fosA 基因的革兰氏阴性病原体的活性。使用 根据 ANY1-FosA X 射线晶体结构的见解，我们设计并制备了一种类似物，其具有 ~10X 更大的效力，表明SAR的进一步发展是可能的。本提案的目标是 (1) 药用 FosA 抑制剂的化学优化，(2) ADME 特性的评估和优化，以及 (3) 生物 针对广泛的 XDR 革兰氏阴性临床分离株进行评估。我们预计这样的组合 可用于治疗侵袭性感染，包括菌血症、肺炎、腹腔内感染和 由含有 fosA 的革兰氏阴性菌（例如肺炎克雷伯菌、肠杆菌属、 铜绿假单胞菌），包括极度耐药的菌株。在此第一阶段提案中，我们将确定并评估 基于 ANY1 的 FosA 抑制剂，结合了制药和药物化学专业知识 福克斯蔡斯化学多样性中心 (FCCCDC) 的科学家们拥有 匹兹堡大学 Sluis-Cremer 实验室从事 FosA 抑制和抗生素实验方面的研究 治疗。