A comparative metabologenomic approach reveals mechanistic insights into <i>Streptomyces</i> antibiotic crypticity
Yunci Qi, Keshav K. Nepal, Joshua A. V. Blodgett
Abstract
Significance Streptomyces genomes harbor a trove of biosynthetic gene clusters (BGCs) that encode for drug-like molecules. However, only a fraction of these readily yield expected products. To investigate why this is, we used polycyclic tetramate macrolactam (PTM) antibiotic production as a model system. By comparing the genomes and PTM production profiles of several closely related Streptomyces griseus clade members, we uncovered two mechanisms that differentiate more robust producers from weaker ones. The first involves small insertion–deletion lesions in PTM BGC promoters that significantly modulate production. The second mechanism involves biosynthetic pathway interactions, in which robust PTM producers unexpectedly benefit from griseorhodin coproduction, and weaker producers lack the pathway. We highlight comparative metabologenomics as a powerful approach to understand antibiotic crypticity.