| Summary: | Empedopeptins—eight amino acid cyclic lipopeptides—are calcium-dependent antibiotics that act against Gram-positive bacteria such as <i>Staphylococcus aureus</i> by inhibiting cell wall biosynthesis. However, to date, the biosynthetic mechanism of the empedopeptins has not been well identified. Through comparative genomics and metabolomics analysis, we identified empedopeptin and its new analogs from a marine bacterium, <i>Massilia</i> sp. YMA4. We then unveiled the empedopeptin biosynthetic gene cluster. The core nonribosomal peptide gene null-mutant strains (Δ<i>empC</i>, Δ<i>empD</i>, and Δ<i>empE</i>) could not produce empedopeptin, while dioxygenase gene null-mutant strains (Δ<i>empA</i> and Δ<i>empB</i>) produced several unique empedopeptin analogs. However, the antibiotic activity of Δ<i>empA</i> and Δ<i>empB</i> was significantly reduced compared with the wild-type, demonstrating that the hydroxylated amino acid residues of empedopeptin and its analogs are important to their antibiotic activity. Furthermore, we found seven bacterial strains that could produce empedopeptin-like cyclic lipopeptides using a genome mining approach. In summary, this study demonstrated that an integrated omics strategy can facilitate the discovery of potential bioactive metabolites from microbial sources without further isolation and purification.
|
|---|