Armeniaspirols, A new class of Gram-positive antibiotics that target Clp proteases
The emergence of multi-drug resistant bacteria in the clinic presents major challenges to managing human health and threatens the great progress that has been made in preventing morbidity and mortality in the age of antibiotics. In order to combat these pathogens, new antibiotics with diverse mechanisms of action are required. Armeniaspirols represent a novel class of natural product-based bacteriostatic antibiotics with an unknown mechanisms of action. In this talk we will disclose the mechanism of action of armeniaspirol. Using total synthesis, analogs of armeniaspirol were synthesized and their antibiotic properties examined. A combination of chemoproteomics, quantitative proteomics, and a battery of functional assays were used to discover that aremeniaspirols directly inhibit the AAA+ proteases ClpYQ and ClpXP, leading to dysregulation of the divisome and ultimately antibiotic activity. Our in vitro biochemical results were validated by in vivo by comparisons with genetic knockouts. Sub-lethal antibiotic challenges further suggested that the development of resistance to aremiaspirol inhibition of ClpYQ and ClpXP is difficult to achieve without negative consequences for the bacteria, thus resistance does not readily arrise. Synthesis of a battery of armeniaspirol analogs, followed by characterization of their biochemical activity against Clp proteases as well as minimum inhibitor and bactericidal concentrations against multidrug resistant Staphylococcus aureus has enabled the discovery of analogs with significantly enhanced potency and bactericidal activity without detectable toxicity to mammalian cells. Lastly, we show through characterization of the armeniaspirol biosynthetic pathway that an advanced, though structurally distinct biosynthetic precursor is also highly antibiotic. Intriguingly, it appears to inhibit a different target, providing a snapshot of how complex biosynthetic pathways may evolve. The armeniaspirols thus represent an important new scaffold to combat multi-drug resistant bacterial infections, through a potent and highly novel mechanism of action, and provide a rich avenue for studying the evolution of complex bioactive natural products.
Speaker Biography
Christopher Boddy received a BSc from the University of Alberta in 1995 and a PhD at The Scripps Research Institute in 2001 under the direction of K. C. Nicolaou. He was a post-doctoral Fellow at Stanford University working with Chaitan Khosla from 2001– 2004. In 2004 he joined the Department of Chemistry at Syracuse University and in 2008, he moved to the University of Ottawa, Department of Chemistry and Biomolecular Sciences where he is currently a full professor and director of the undergraduate biochemistry program. His research program focuses on the chemistry, biosynthesis, and pharmacology of natural products and bioactive compounds. More information about Boddy’s research program can be found at http://www.boddylab.ca.