Widespread antibiotic use has accelerated S. aureus resistance to almost all marketed antibiotic classes including beta-lactams, fluoroquinolones, macrolides, aminoglycosides, tetracyclines, as well as the newer linezolid and daptomycin. Methicillin-resistant S. aureus (MRSA) is an increasing public health threat, with deaths from MRSA infections already comparable to HIV/AIDS in 2005, and increasing since then. Thus, there is a clear imperative for developing new therapeutic agents. In recent work, we have developed antimicrobial compounds that show low micromolar antibacterial activity against both wild type and methicillin-resistant S. aureus through dual mechanism activity - initially inducing rapid depolarization of bacterial membranes, followed by cell penetration and target-based bacterial killing through inhibition of the enzyme enoyl reductase, or FabI. Our inhibitors show mid- to low-nanomolar inhibition of FabI, with promising metabolic stability and cytotoxicity for our initial compounds. Based on extensive preliminary studies, including crystal structures of multiple inhibitors co-crystallized with FabI, mechanistic characterization of a unique mode of inhibition, and characterization of inhibitor metabolic stabilities, we now propose to develop improved antimicrobial agents through an iterative process of determining detailed structure-based molecular design, synthetic medicinal chemistry, initial preclinical toxicology, and pharmacokinetic characterization, with specific proposed milestones and go/no-go criteria. The goal of this Phase I STTR application is to develop proof of concept for antibacterial lead compounds against drug resistant S. aureus that are safe and efficacious.
Public Health Relevance Statement: Public Health Relevance: Widespread antibiotic use has accelerated drug resistance in the bacterium Staphylococcus aureus to almost all marketed antibiotic classes including beta-lactams, fluoroquinolones, macrolides, aminoglycosides, tetracyclines, as well as the newer linezolid and daptomycin. Methicillin-resistant S. aureus (MRSA) is an increasing public health threat, with deaths from MRSA infections already comparable to HIV/AIDS in 2005, and increasing since then. Our research will utilize a combination of computational chemistry, enzymology, X- ray crystallography, synthetic medicinal, mutational resistance analysis and preclinical biological studies to develop inhibitors of an enzyme in the fatty acid biosynthetic pathway that is called enoyl reductase or FabI. We are developing these as new potential drugs for the treatment of S. aureus and its drug resistant strain, MRSA.
Project Terms: Achievement; Active Sites; Affinity; AIDS/HIV problem; Aminoglycosides; animal efficacy; Animals; Anti-Bacterial Agents; Antibiotics; antimicrobial; antimicrobial drug; Bacteria; base; benzimidazole; Benzimidazoles; beta-Lactams; Binding (Molecular Function); Biodistribution; Biological; Biological Availability; Cell membrane; Cells; Cessation of life; Chemicals; cofactor; computational chemistry; cytotoxicity; Daptomycin; Data; design; Development; Dose; Drug Kinetics; Drug resistance; efficacy testing; enoyl reductase; Ensure; Enzymatic Biochemistry; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exhibits; Fatty Acids; Fluoroquinolones; Goals; Half-Life; Health; Hydrogen Bonding; improved; in vivo; Infection; inhibitor/antagonist; Killings; Lead; Linezolid; Macrolides; Maps; Marketing; Membrane; Metabolic; Metabolism; Methicillin; methicillin resistant Staphylococcus aureus (organism); Modeling; Molecular; multidisciplinary; Mus; NADP; next generation; novel; novel therapeutics; Oral; Pathway interactions; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Plasma Proteins; Positioning Attribute; pre-clinical; Predisposition; Process; Property; Protein Binding; public health medicine (field); Regimen; Research; Resistance; Resistance development; resistant strain; Roentgen Rays; scaffold; Series; Site-Directed Mutagenesis; Small Business Technology Transfer Research; Solubility; Solutions; Staphylococcus aureus; Structure; Testing; Tetracyclines; Therapeutic Agents; TimeLine; Toxic effect; Toxicology; Work; X-Ray Crystallography
