The overall goal of this project is to conduct preclinical studies on Novo29, our newly-discovered bactericidal compound. As drug-resistance continues to spread, new classes of antibiotics are needed to combat infections by pathogens such as methicillin resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE). Novo29 is a novel class of peptidoglycan synthesis inhibitor with favorable drug properties. It shows excellent activity against Gram-positive pathogens, has not shown resistance to date, and is well tolerated in mice. Interestingly, Novo29 shares structural features with teixobactin, another new class of antibiotic that we discovered in 2015. Teixobactin, which is currently in development, kills bacteria by binding to two bacterial cell wall precursors (lipid II and lipid III), and no resistance to the compound has been shown. Part of this grant will examine whether Novo29 works through the same mechanism as teixobactin. Although structurally similar, Novo29 may offer an advantage over teixobactin as it is a smaller compound (902D compared to 1242D), and does not gelate in serum, which has narrowed teixobactinÂ’s safety window. In Aim 1, Novo29 will be tested against an expanded panel of important pathogens, including contemporary clinical isolates. Time-kill profiles and expanded resistance studies effects will be studied in relevant pathogens. In addition, we will determine protein binding and microsomal stability of Novo29. In Aim 2, Novo29 will be tested for binding to the lipid II and lipid II precursors. If Novo29 does not bind to these compounds, we will analyze the accumulation of peptidoglycan nucleotide precursors and perform muropeptide analysis of Novo29-treated cells to identify the target. Finally, in Aim 3 we will conduct pharmacokinetic studies in mice that will inform the design of an efficacy study in a mouse thigh infection model using MRSA. The vast majority of antibiotics entering the market over the last several decades are simply incremental modifications of known structures. As resistance to common scaffolds is a major health concern, our discovery of yet another antibacterial compound with novel structure and important mode of action meets a critical, unmet goal in antibiotic drug discovery. In this project, Novo29 will advance through early preclinical studies in preparation for Investigational New Drug (IND)-enabling studies.
Public Health Relevance Statement: NARRATIVE One of our most serious health threat is the loss of effective antibiotics due to antimicrobial resistance. The preclinical development of a newly discovered antibiotic in this proposed study addresses the urgency of this problem.
Project Terms: Acute; Address; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Bacteremia; Bacteria; bactericide; Binding; Binding Proteins; Cell Wall; Cells; Clinical; combat; cytotoxicity; design; Development; drug discovery; Drug Kinetics; Drug resistance; efficacy study; Evaluation; Formulation; Goals; Grant; Health; Hospitals; In Vitro; in vitro testing; in vivo; Infection; inhibitor/antagonist; Investigational Drugs; Killings; Lipid Binding; Lipid III; Lipids; Metabolic; methicillin resistant Staphylococcus aureus; microbiota; microorganism; Modeling; Modification; Molecular; Multi-Drug Resistance; Mus; mutant; novel; Nucleotides; pathogen; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pneumonia; preclinical development; preclinical study; Preparation; Property; Proteobacteria; Resistance; Safety; scaffold; Serum; Skin; Solubility; Staphylococcus aureus; Structure; Tail; Technology; Teichoic Acids; Testing; Thigh structure; Time; Vancomycin resistant enterococcus; Ventilator; Work
