Bacterial polyketides are a rich source of chemical diversity and pharmaceutical agents. Understanding the biochemical basis for their biosynthesis and the evolutionary driving force leading to this diversity is essential to take advantage of the enzymes as biocatalysts and to access new chemical diversity for drug discovery. Biochemical characterization of the thioesterase (TE) responsible for 6-deoxyerythronolide macrocyclization shows that a small, evolutionarily accessible change to the substrate can increase the chemical diversity of products, including macrodiolide formation. We propose an evolutionary model in which TEs are by nature non-selective for the type of chemistry they catalyze, producing a range of metabolites. As one metabolite becomes essential for improving fitness in a particular environment, the TE evolves to enrich for that corresponding reactivity. This hypothesis is supported by our phylogenetic analysis, showing convergent evolution of macrodiolide-forming TEs.

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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 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. Herein, we synthesized analogs of armeniaspirol and studied their antibiotic properties and mechanism of action. Using a combination of chemoproteomics, quantitative proteomics, and a battery of functional assays we discovered that armeniaspirols inhibit the bacterial divisome through direct inhibition of the ClpYQ and ClpXP proteases. This was validated by comparisons with genetic knockouts. Sub-lethal challenges suggested that resistance to armeniaspirol inhibition of ClpYQ and ClpXP proteases was difficult to achieve without catastrophic consequences for the bacteria. Thus, the armeniaspirols represent an important new tool to combat multi-drug resistance, through a potent and highly novel mechanism of action.

To combat antimicrobial resistance, antibiotics with fundamentally new mechanisms of action, like armeniaspirol, which targets the ATP-dependent proteases ClpXP and ClpYQ, must be developed. While the mechanism of action of...

The Streptomyces genus represents a prolific and significant source for secondary metabolite discovery. Here, we report a de novo assembly and draft genome sequence for the type strain Streptomyces armeniacus ATCC 15676.