Grant: Operating Grant

The World Health Organization (WHO) has recently classified antibiotic resistance as one of the three greatest threats to human health. Amongst antibacterial agents, aminoglycosides occupy a special niche due to their effectiveness against most bacteria, including the causing agent of tuberculosis. The long term goal of this project is to find agents to overcome aminoglycoside resistance. To achieve this, our efforts will focus on 3 streams: 1) study one of the most common determinants of aminoglycoside resistance, aminoglycoside N-6'-acetyltransferase (AAC6'); 2) design molecules that block resistance caused by AAC(6'); and 3) design new antibacterial agents active against resistant strains. A better understanding of resistance-causing mechanisms is critical to the development of resistance inhibitors and of antibacterials active against resistant strains. We have made significant progress in this area. We have also reported the first AAC(6') inhibitor able to block aminoglycoside resistance in cells as well as the first prodrugs with such an activity. Finally, we have recently reported some molecules with activity against antibiotic resistant bacteria. One of these is especially active and will be studied further. The main goal of this research project is to improve the potency and pharmaceutical properties of our most active molecules. To this end, medicinal chemistry studies will include the synthesis of multiple derivatives, followed by biological studies with purified enzymes, in cells or in animals.