?Infections caused by antibiotic-resistant bacteria continue to be a growing challenge in the community and hospital setting. A group of bacteria known as the "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) cause the majority of hospital infections. The growing need for novel antibacterial drugs has been well highlighted by agencies such as the Infectious Diseases Society of America (IDSA), U.S. Congress, FDA, CDC, and NIH. Novel antibacterials that inhibit unexploited targets are desperately needed to address untreatable infections that arise from drug-resistant pathogens. LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase) has emerged as an attractive target for antibacterial development as it catalyzes the committed step of lipid A biosynthesis required for virtually all Gram-negative bacteria. Bacteria lacking lipid A are not viable and mutants with reduced lipid A are hypersensitive to antibacterials. Therefore, a potent inhibitor of LpxC will be effective at treating Gram-negative infections. Forge Therapeutics is utilizing a novel chemistry approach to target LpxC. Our approach is differentiated from existing efforts in industry and academia, because Forge employs a unique method to identify optimal metal-binding pharmacophores (MBPs) that have a specific affinity for the metalloenzyme active site of interest. Traditional medicinal chemistry efforts shy away from different MBPs allowing Forge to pioneer this new approach, making gains in a field that has struggled to tackle the challenges associated with metalloprotein inhibition. The unparalleled know-how possessed by our scientific leadership team, founders, and experienced consultants will allow Forge to rapidly and efficiently advance our novel molecules from discovery to validation. Phase II Strategy. After completion of the Specific Aims in this Phase I proposal, the goals for Phase II will focus on: a) additional optimization and in vitro studies, b) further MIC screens against multiple strains and human metalloprotein cross-reactivity screens, and c) resistance mutant generation and spontaneous mutant frequency. Finally, of the compounds that advance through this round of in vitro testing, we will select a set to be analyzed in vivo using a validated rodent efficacy model.
Public Health Relevance Statement: Public Health Relevance: Drug resistant Gram-negative bacteria pose a persistent health threat and are a major cause of mortality and morbidity throughout the world. Novel antibacterials that inhibit unexploited targets are desperately needed to address untreatable infections that arise from drug-resistant pathogens. Forge Therapeutics will use an innovative approach to address the challenge of antibiotic resistance by discovering novel inhibitors of bacterial metalloenzyme LpxC.
Project Terms: Academia; Acinetobacter baumannii; Active Sites; Address; Affinity; Americas; Anabolism; Animals; Anti-Bacterial Agents; Antibiotic Resistance; antimicrobial; Bacteria; base; Binding; Budgets; Centers for Disease Control and Prevention (U.S.); Chemistry; Communicable Diseases; Community Hospitals; compound 30; Congresses; cross reactivity; Crystallography; Deacetylase; design; Development; Drug Design; Drug Kinetics; Drug resistance; Enterobacter; Enterococcus faecium; Enzymatic Biochemistry; Enzymes; Escherichia coli; Evaluation; experience; forging; Frequencies; Future; Generations; Goals; Gram-Negative Bacteria; Health; Human; improved; In Vitro; in vitro testing; in vivo; Industry; Infection; inhibitor/antagonist; innovation; interest; Klebsiella pneumonia bacterium; Leadership; Libraries; Lipid A; Measurement; metalloenzyme; Metalloproteins; Metals; Methods; Microbiology; Modeling; Morbidity - disease rate; mortality; Multi-Drug Resistance; mutant; Nosocomial Infections; novel; novel strategies; pathogen; Pharmaceutical Chemistry; Pharmaceutical Preparations; pharmacophore; Phase; physical property; Property; Pseudomonas aeruginosa; public health relevance; Resistance; Rodent; screening; Screening Result; small molecule inhibitor; Societies; Staphylococcus aureus; structural biology; Structure; Synthesis Chemistry; Testing; Therapeutic; TimeLine; United States National Institutes of Health; Validation; X-Ray Crystallography
