Grant: Operating Grant

Modern medicine depends on our ability to control bacterial infections. At present the only way to do this is to administer antibiotics. This is important for treating routine infections such as bacterial pneumonia, meningitis, ear and upper respiratory infections (especially in children) and for managing infections that arise post-surgically and due to immune suppression resulting from disease and chemotherapy. More than 80 million antibiotic prescriptions are given each year in North America alone. The rapid rise in antibiotic-resistant infections is therefore an extremely serious problem. Resistance has emerged and proliferated within a few years of the introduction of every single antibiotic. Where does this resistance come from? How does it arise and spread so quickly? Growing evidence strongly suggests that resistance for most or all of the antibiotics exists already in Nature. This is because the antibiotics themselves come from Nature - most of them are purified from soil bacteria. There is no ready alternative source of antibiotics so we are stuck with this sorce of theraputic agents. But if we could understand these antibiotic resistance mechanisms before they arise it would allow us to use antibiotics more intelligently, reduce clinical resistance and increase efficacy. Furthermore, we could develop resistance protein inhibitors that would restore the usefulness of those drugs subject to widespread resistance. Our research suggests that the large family of bacterial transcription factors known as TetR-like proteins (TLPs) and the genes ("effectors") that they regulate are a large component of this uncharacterized environmental resistance. Our plan is to identify the antibiotics that they act on and understand their biological importance. We will argue that this work will provide new ways of combating antibiotic resistance and facilitate antibiotic discovery.