Grant: Collaborative Health Research Projects

The acquisition of bacterial resistance to conventional antibiotics represents a major threat to human health.Daptomycin (DAP) is a cyclic lipopeptide antibiotic (LPA) that kills bacteria through membrane damage. It isused to treat a broad range of infections caused by Gram-positive bacteria, including ones that have becomeresistant to other types of antibiotics. As the development of DAP resistance in certain Gram-positive bacteriahas been reported, concerns about decreasing clinical effectiveness of DAP have to be addressed. Anotherissue with DAP is that it is inhibited by lung surfactant, which compromises its effectiveness for treatingpneumonia.The objectives of the proposed research are to prepare DAP analogs with increased potency and to learn moreabout the mechanism of action of DAP. The 3-D structure of membrane-associated DAP will be determined byhigh resolution NMR spectroscopy (Dieckmann). Multimeric forms of DAP will be prepared (Dmitrienko),and combinatorial total synthesis will be used to prepare libraries of DAP analogs (Taylor). Analogs that areactive against a model Gram-positive bacterium, Bacillus subtilis will be tested against a broad range ofDAP-susceptible and DAP-resistant Gram-positive pathogens (Pillai). Functional studies on DAP interactionwith membranes will be performed by cross-linking and fluorescence (Palmer). The results from these studieswill provide crucial information on the mechanism of action of DAP and hopefully provide DAP analogs withsuperior potency in both the absence and presence of surfactant and good potency against resistant strains.