Grant: Proof of Principle Program - Phase I

Methicillin-resistant Staphylococcus aureus (MRSA) is causing dramatic increases in the incidence of antibiotic resistant infections in Canadian hospitals and across the globe. Disturbingly, resistant pathogens such as MRSA are now also emerging in the community, infecting persons of all ages often with no apparent risk factor. MRSA strains are usually resistant to multiple drug classes (beta-lactams, macrolides, aminoglycosides, tetracyclines) and resistance to vancomycin, the last efficient drug against this pathogen, is already reported since 2002. The three major problems caused by MRSA are mortality, wasted time and cost for the healthcare system. The development of a novel class of antibiotics that tackles MRSA infections would be most welcome. Recently, our research led to the discovery of a new antibacterial target that is shared among some bacterial pathogens and that is absent from the mammalian host. Of special interest, this new target is an RNA molecule with a regulatory function (a guanine riboswitch) that is essential to certain bacteria. Our work also led to the identification of a small-molecule ligand with drug-like properties able to bind the guanine riboswitch and prevent expression of essential genes with subsequent bactericidal action. We further demonstrated the antibacterial activity of one of such antibiotic compounds in experimental therapies for Staphylococcus aureus intra-mammary infections (mastitis) in mice and cows. The general objective of this research proposal is to provide the necessary proof of principle to further develop novel and potent antibiotics to control infections in humans caused by the antibiotic multi-resistant superbug MRSA. The demonstration of compound efficacy in animal models that are relevant to MRSA infection in humans (CIHR-POP, Phase I) will reduce the risks associated with the commercialization of these molecules and attract a partner for Phase II.