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.

总结。抗微生物药物耐药性被广泛认为是最严重的公共卫生威胁之一