Preclinical development of Novo29, a new antibiotic

Abstract The overall goal of this project is to conduct preclinical studies on Novoour newly discovered bactericidal compoundAs drug resistance continues to spreadnew classes of antibiotics are needed to combat infections by pathogens such as methicillin resistant Staphylococcus aureusMRSAand vancomycin resistant EnterococciVRENovois a novel class of peptidoglycan synthesis inhibitor with favorable drug propertiesIt shows excellent activity against Gram positive pathogenshas not shown resistance to dateand is well tolerated in miceInterestinglyNovoshares structural features with teixobactinanother new class of antibiotic that we discovered inTeixobactinwhich is currently in developmentkills bacteria by binding to two bacterial cell wall precursorslipid II and lipid IIIand no resistance to the compound has been shownPart of this grant will examine whether Novoworks through the same mechanism as teixobactinAlthough structurally similarNovomay offer an advantage over teixobactin as it is a smaller compoundD compared toDand does not gelate in serumwhich has narrowed teixobactin s safety windowIn AimNovowill be tested against an expanded panel of important pathogensincluding contemporary clinical isolatesTime kill profiles and expanded resistance studies effects will be studied in relevant pathogensIn additionwe will determine protein binding and microsomal stability of NovoIn AimNovowill be tested for binding to the lipid II and lipid II precursorsIf Novodoes not bind to these compoundswe will analyze the accumulation of peptidoglycan nucleotide precursors and perform muropeptide analysis of Novotreated cells to identify the targetFinallyin Aimwe will conduct pharmacokinetic studies in mice that will inform the design of an efficacy study in a mouse thigh infection model using MRSAThe vast majority of antibiotics entering the market over the last several decades are simply incremental modifications of known structuresAs resistance to common scaffolds is a major health concernour discovery of yet another antibacterial compound with novel structure and important mode of action meets a criticalunmet goal in antibiotic drug discoveryIn this projectNovowill advance through early preclinical studies in preparation for Investigational New DrugINDenabling studies NARRATIVE One of our most serious health threat is the loss of effective antibiotics due to antimicrobial resistanceThe preclinical development of a newly discovered antibiotic in this proposed study addresses the urgency of this problem