The rapid emergence of multidrug resistant bacteria is a major global concern. A 2014 report by the UK government estimates that by 2050, antibiotic resistance will cause 300 million premature deaths, result in a loss of up to $100 trillion from the global economy and cause more premature deaths than cancer. Therefore, there is a pertinent need for new antimicrobial compounds and targets.
Mechanistic Studies on Glycolipid Flippases
Bacteria produce several polysaccharides that are essential to their structural integrity, including peptidoglycan and lipopolysaccharide. As the enzymes and intermediates involved in their biosynthesis are unique to bacteria, they are excellent antibiotic targets. In particular, the mechanism by which glycolipids are transported across cell membranes (by flippases) is poorly understood. Our lab uses the tools of organic synthesis to prepare glycolipid substrates for probing the mechanism of action of these enzymes, as well as using structure-activity relationship studies to guide inhibitor design, with the goal of developing new antibiotic candidates.
Novel Syntheses of Antimicrobial Peptides
Antimicrobial peptides produced by bacteria are becoming increasingly important in the fight against multidrug resistance. These compounds typically target bacterial cell membranes, and as it is difficult for bacteria to reorganize their membranes, resistance development is often limited. Our lab develops new synthetic methods to access novel antimicrobial peptides, allowing their antimicrobial and/or anticancer activities to be explored. We also use molecular biology and bioinformatics to identify the mechanism by which they exert their therapeutic effect.
Antimicrobial Peptide Resistance Mechanisms
Although resistance mechanisms against antimicrobial peptides are limited, they are not resistance-proof. Understanding resistance mechanisms against antibiotics is important, as it can allow us to circumvent these mechanisms and restore activity. In the Cochrane Lab, we are particularly interested in enzymes that sequester the activity of antimicrobial peptides by chemically capping basic residues. Using a combination of organic synthesis, molecular biology and bioinformatics, we identify and study these enzymes, with the goal of determining their mechanism of action, as well as designing inhibitors to block their activity.