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.
Public Health Relevance Statement: In this application we propose to carry-out hit to lead and lead optimization SAR development of FosA inhibitors to be used in combination with the established antibiotic drug fosfomycin to expand its therapeutic use. The fosA gene is chromosomally encoded by many clinically relevant Gram-negative pathogens (e.g. Pseudomonas aeruginosa and Klebsiella pneumoniae) and confers resistant to the fosfomycin. FosA inhibitors would potentiate FOM activity to treat invasive infections including bacteremia, pneumonia, intra-abdominal infections and complicated UTIs caused by Gram-negative bacteria that harbor fosA, including extremely drug resistant strains.
Project Terms: absorption; Klebsiella pneumoniae; K pneumoniae; K. pneumoniae; inhibitor; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Bacteremia; bacteraemia; bacterial sepsis; Bacteria; Bacterial Infections; bacteria infection; bacterial disease; Bacterial Pneumonia; bacteria pneumonia; Biological Assay; Assay; Bioassay; Biologic Assays; Carbon; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Crystallization; Drug Industry; Pharmaceutic Industry; Pharmaceutical Industry; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Enterobacter; Aerobacter; Epoxy Compounds; Epoxides; Escherichia coli; E coli; E. coli; Fosfomycin; Phosphonomycin; Foxes; Future; Genes; Glutathione; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; Glutathione S-Transferase; EC 2.5.1.18; Glutathione Organic Nitrate Ester Reductase; Glutathione S-Alkyltransferase; Glutathione S-Aralkyltransferase; Glutathione S-Aryltransferase; Glutathione S-Epoxidetransferase; Glutathione Transferase; Heme Transfer Protein; Ligandins; S-Hydroxyalkyl Glutathione Lyase; glutathione aralkyltransferase; glutathione aryltransferase; Goals; Gram-Negative Bacteria; Hospitals; Human; Modern Man; Infection; Metabolism; Intermediary Metabolism; Metabolic Processes; Patents; Legal patent; Pharmacokinetics; Drug Kinetics; Pneumonia; Production; Proteins; P aeruginosa; P. aeruginosa; Pseudomonas pyocyanea; Pseudomonas aeruginosa; Public Health; Records; Research; Safety; Transferase; Transferase Gene; Universities; Urinary tract infection; Urinary tract infectious disease; urinary infection; Roentgen Rays; X-Radiation; X-Ray Radiation; X-ray; Xray; Measures; Mediating; Ventilator; base; Acute; Clinical; Penetration; Phase; Biological; biologic; Ensure; Chemicals; Evaluation; Susceptibility; Predisposition; excretion; Excretory function; insight; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; analog; Antibiotic Treatment; bacterial disease treatment; bacterial infectious disease treatment; Antibiotic Therapy; Intravenous; Scientist; Oral; Route; dimer; experience; success; nucleophilic addition; pharmacophore; Toxicities; Toxic effect; Structure; novel; Property; drug development; drug discovery; Abdominal Infection; Molecular Interaction; Binding; Therapeutic Uses; GeneHomolog; Homolog; Homologue; Homologous Gene; Antimicrobial resistant; Resistance to antimicrobial; anti-microbial resistance; anti-microbial resistant; resistance to anti-microbial; resistant to anti-microbial; resistant to antimicrobial; Antimicrobial Resistance; Affinity; Data; Intra-abdominal; NIAID; National Institute of Allergy and Infectious Disease; in vitro Assay; Small Business Technology Transfer Research; STTR; Process; Adjuvant; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; design; designing; novel strategies; new approaches; novel approaches; novel strategy; scale up; Resistance development; Resistant development; developing resistance; pathogen; Resistance; resistant; antimicrobial; anti-microbial; clinically relevant; clinical relevance; iterative design; combat; resistant strain; resistance strain; in vitro activity; Drug Targeting; Industry Standard; Formulation; small molecule inhibitor; lead optimization; Lung infections; pulmonary infections
