Grant: Discovery Grants Program - Individual

The emergence and spread of antibiotic resistant bacteria has raised many concerns regarding our ability to treat infections caused by them. This has reinvigorated research into the discovery of new antibiotics and for devising strategies to treat such infections. Some of the best solutions for combating bacterial pathogens come from nature in the form of natural products, which also include chemical compounds produced by other bacteria. Most of these compounds are synthesized using specialized pathways and sets of genes, which are mostly present is certain groups of microorganisms. The -lactam family of natural products includes members such as the penicillin and cephalosporin antibiotics, which have a long history of human use. They are also the most widely used class of antibiotics, but -lactam resistance has always posed a challenge. Certain enzymes can chemically inactivate penicillin and cephalosporin antibiotics to cause resistance. Clavulanic acid is a naturally produced inhibitor of such enzymes, and when used in combination with a penicillin-type antibiotic, it restores the ability of the antibiotic to act against the otherwise resistant pathogen. Clavulanic acid is industrially produced using the bacterium Streptomyces clavuligerus. The biosynthetic pathway leading to clavulanic acid production is only partially known, and details regarding all of the genes involved in the process are also lacking. The Streptomyces are known to produce many medicinally important compounds and there is great interest in studying them with the aim of finding ways to improve natural product yields and to identify new molecules. Within the last two decades it has been found that the Streptomyces contain predicted genes for potentially making many natural products, but only a few are produced under laboratory conditions. Therefore, these so called "unknown or cryptic" natural products could be sources of future drugs for human and veterinary use. The long term goal of my work is to fully understand the mechanisms controlling the biosynthesis of clavulanic acid and other natural products in S. clavuligerus and related bacteria. This research program will contribute significantly in the generation of knowledge that can be used to produce molecules for novel applications. In addition, it will train students and other highly qualified personnel, which will benefit Canada by providing access to individuals skilled in the discovery and analysis of natural products.