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Abstract:

The emergence of multi-drug resistant organisms clinically presents major challenges to managing human health and threaten 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 will be required. Armeniaspirols represent a novel class of natural product-based antibiotic molecules with 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 resistance to aremiaspirol inhibition of ClpYQ and ClpXP is difficult to achieve without catastrophic consequences for the bacteria. Lastly, we show through characterization of the armeniaspirol biosynthetic pathway that an advanced though structurally distinct biosynthetic precursor is also highly antibiotic. Intriguingly, it inhibits a different target providing a snapshot of how complex biosynthetic pathways may evolve. The armeniaspirols thus represent an important new tool to combat multi-drug resistance, through a potent and highly novel mechanism of action and provide a rich avenue for studying the evolution of complex bioactive natural products.

Bio:

Christopher Boddy is a professor in the Chemistry and Biomolecular Sciecnes department at the University of Ottawa and the director of the Biochemistry program. Through his PhD with KC Nicolaou in synthetic organic chemistry, he developed a love of complex bioactive natural products, which was only deepened by studying natural product biosynthesis with Chaitan Khosla. His research program at the interface of chemistry, biology, and microbiology focuses on the synthesis, biosynthesis, and function of complex polyketide and non-ribosomal peptide natural products.