Antimicrobial Resistance Determinants

The development of antimicrobial resistance is a medical problem of global proportions; which increasingly is thwarting our abilities to treat infectious diseases. To combat this global threat there is a need for research into the development of new antibiotics. We are working to elucidate the mechanisms by which bacteria sense antibiotics and respond by expressing genes that confer antibiotic resistance.

Resistance genes are generally regulated by transcription factors: proteins that bind the DNA upstream of the genes to either block or facilitate their expression. We are attempting to determine the structures of repressors that block the expression of resistance genes in bacterial pathogens such as Neisseria gonorrhoea and Vibrio cholerae. In combination with these structural studies we employ biochemical analyses on the dynamics of the interaction of the repressors with drugs and DNA. These studies will provide fundamental information on how these proteins respond to antibiotics to control the expression of resistance genes. We are also involved in developing fluorescence assays to monitor antibiotic-repressor interactions for use as novel biosensors to screen for new antibiotics.

Resistance is often conferred by proteins that act like bilge pumps, lowering the amount of drug inside the cell to a non-toxic level. These protein pumps, which are inserted into the cell membrane, have a site that recognizes the drug and transports it across the membrane out of the cell. The goal of our research is to discover how these protein pumps work, so we can design transport inhibitors to block drug-efflux, allowing a renaissance in the use of drugs, no-longer effective in treating microbial infections.