Chemical genetic dissection of an unusual animalcule
Van Leeuwenhoek Lecture on BioScience.
Justin Nodwell obtained his PhD in molecular biology at the University of Toronto (1993), he was a postdoc at Harvard (1993-1998), went to Mcmaster University (1998-2013) and was appointed professor of Biochemistry at the University of Toronto (2013).
His group studies the way in which bacterial cells respond to chemicals; the focus is on streptomycetes, known for their secondary metabolism, which is the source of antibiotics, chemotherapeutics, antifungals and many other drugs. Paradoxically, streptomycetes produce antibacterial compounds without killing themselves: which are the mechanisms that allow this to happen?
The research of Nodwell's group is fundamental (the chemical biology of microbial life) as well as directed to the quest for new medicines.
The Streptomycetes bacteria have an unusual filamentous morpology that sets them apart from other prokaryotes. Their life cycle starts with spore germination and the generation of filamentous "substrate hyphae" that grow to form a vegetative colony. Later, developmental cues trigger the formation of another cell type called the "aerial hyphae" which grow up from the colony surface and eventually generate a new germination of spores. An unusual feature of two cell types is that they usefundamental cell biological processes in unusual ways. For example, the cell wall synthesis, cell division and chromosome segregation apparatus are deployed differently in both cell types than in the more rod shaped or coccoid bacteria. Another feature that sets these bacteria apart is their extensive 'secondary" or "specialized" metabolism which generates a very large set of biologically active small molecules. These molecules have served as a reservoir of lead compounds for drug discovery.
We have investigated the interactions of streptomyces bacteria with biologically active small molecules. In this lecture I will discuss how we have used these chemical probes to perturb the regulation of secondary metabolism and the sporulation pathway. In addition to generating novel antibiotic leads this work is providing new insights into the molecular mechanisms that control the life cycle of this remarkable genus.
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