Reference number : GC-2017-Q1-01845, amendment number : , agreement type : G, recipient legal name : Taylor, Scott (University of Waterloo), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : One of the most important advances in modern medicine was the discovery of antibiotics. Unfortunately, bacteria have developed, or are beginning to develop, resistance to many antibiotics, including what are called last-defence antibiotics: a small number of antibiotics that are effective when all of the other more common antibiotics fail. Hence, the World Health Organization has identified antimicrobial resistance as one of the three most important problems for human health. The majority of this research proposal deals with the development of new antibiotics. We use as our starting point a cyclic lipopeptide antibiotic (cLPA) called daptomycin (Dap). Dap is an important, last-defence antibiotic used to treat complicated infections caused by Gram positive bacteria. However, resistance to Dap is beginning to appear. One of the goals of this proposal is to develop cLPAs that are similar to Dap yet are active against bacteria that are resistant to Dap. We have developed a method for chemically synthesizing Dap. This method will be employed to prepare cLPAs that are active against Dap-resistant bacteria. This approach will also be used to develop broad spectrum cLPAs that are active against Gram positive and Gram negative bacteria and can be used for treating bacterial pneumonia. Dap exerts its effect by disrupting bacterial membranes though exactly how it disrupt the membranes is not entirely clear. Consequently, this research effort will be complemented by structure-function studies to determine how Dap disrupts bacterial membranes. The results of these studies will facilitate the design of new cLPAs with improved activity against resistant strains. 
In addition to studies on antibiotics, this proposal also deals with the development of inhibitors of an enzyme called cytidine triphosphate synthase (CTPS), which is an anticancer, antiviral, and antiprotozoal target. CTPS inhibitors will be constructed using phosphorylation chemistry developed in our group. These inhibitors will be used to determine which residues are important for ligand binding and intermediate and transition state stabilization in the CTPS reaction. The results of these studies will provide information that will be crucial for developing drugs that target CTPS., program purpose french : One of the most important advances in modern medicine was the discovery of antibiotics. Unfortunately, bacteria have developed, or are beginning to develop, resistance to many antibiotics, including what are called last-defence antibiotics: a small number of antibiotics that are effective when all of the other more common antibiotics fail. Hence, the World Health Organization has identified antimicrobial resistance as one of the three most important problems for human health. The majority of this research proposal deals with the development of new antibiotics. We use as our starting point a cyclic lipopeptide antibiotic (cLPA) called daptomycin (Dap). Dap is an important, last-defence antibiotic used to treat complicated infections caused by Gram positive bacteria. However, resistance to Dap is beginning to appear. One of the goals of this proposal is to develop cLPAs that are similar to Dap yet are active against bacteria that are resistant to Dap. We have developed a method for chemically synthesizing Dap. This method will be employed to prepare cLPAs that are active against Dap-resistant bacteria. This approach will also be used to develop broad spectrum cLPAs that are active against Gram positive and Gram negative bacteria and can be used for treating bacterial pneumonia. Dap exerts its effect by disrupting bacterial membranes though exactly how it disrupt the membranes is not entirely clear. Consequently, this research effort will be complemented by structure-function studies to determine how Dap disrupts bacterial membranes. The results of these studies will facilitate the design of new cLPAs with improved activity against resistant strains. 
In addition to studies on antibiotics, this proposal also deals with the development of inhibitors of an enzyme called cytidine triphosphate synthase (CTPS), which is an anticancer, antiviral, and antiprotozoal target. CTPS inhibitors will be constructed using phosphorylation chemistry developed in our group. These inhibitors will be used to determine which residues are important for ligand binding and intermediate and transition state stabilization in the CTPS reaction. The results of these studies will provide information that will be crucial for developing drugs that target CTPS., agreement title english : The Development and Study of Novel Lipopeptide Antibiotics and Enzyme Inhibitors, agreement title french : The Development and Study of Novel Lipopeptide Antibiotics and Enzyme Inhibitors, agreement number : RGPIN, agreement value : 225000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada