Genomic Enzymology of Antibiotic Resistance

Resistance to antibiotics is a growing clinical problem. The ability of microbes to evade antibiotics and the lack of new compounds emerging from the pharmaceutical sector means that we must have a thorough understanding of the mechanisms of resistance and its evolution. We are using a strategy termed Genomic Enzymology to study antibiotic resistance in our lab. In this approach, predicted antibiotic resistance genes are identified from available genome sequences or by direct cloning of new resistance elements based on phenotype. This is followed by rigorous structure/function analysis to understand the molecular details of resistance.

Research in this area is focused on 3 areas:

1) Mechanisms of Antibiotic Resistance
2) Reversing Resistance with Small Molecules
3) Origins, Evolution and Sources of Resistance

1) Mechanisms of antibiotic resistance

We are studying the mechanisms of resistance to several classes of antibiotics including the aminoglycosides, glycopeptides, tetracyclines, streptogramins, lipopeptides, and rifamycins. This includes understanding the detailed molecular mechanisms and the structures of antibiotic resistance proteins. In particular, we are focused on enzymes that inactivate the compounds or bypass the molecular target. Our goals are to fully understand the molecular details of resistance using protein structure and function approaches. With this information, we can begin to strategize around methods to block or otherwise avoid these resistance mechanisms

2) Reversing Resistance with Small Molecules

Knowledge of resistance protein structure and function can be used to identify small molecules that inhibit antibiotic resistance mechanisms. These have the potential to reverse antibiotic resistance in clinical settings. We approach this by both synthesizing inhibitors based on our knowledge of resistance mechanism and protein structure (rational drug design) and by using High Throughput Screening (HTS). Working with the McMaster HTS lab ( http://hts.mcmaster.ca/ ), we have access to over 150,000 molecules, state of the art robotics, and assay platforms for high throughput screening.

3) Origins and evolution of antibiotic resistance

Where does antibiotic resistance come from? Understanding this process can help track the emergence and spread of resistance mechanisms and help us to comprehend the forces at work in selection for resistance. We approach this in two ways. First, we are searching the genomes of bacteria for genes that encode homologues of resistance enzymes and studying the enzymology of these to assess their fitness as antibiotic inactivators. Second, we are actively screening environmental organisms for novel resistance phenotypes and identifying new mechanisms. This includes collecting organisms from diverse environments and studying the molecular mechanism of resistance.