Self-Resistance Guided Discovery of a Hybrid Polyketide-Peptide Antibiotic from Vibrio ruber

A biosynthetic gene cluster that produces a putative antibacterial natural product was identified from the genome of Vibrio ruber DSM 16370 based on its colocalization with a gene encoding an aminoacyl-tRNA synthetase homologue. Biological assays confirmed that the biosynthetic pathway produced an antibacterial metabolite while also verifying assignment of the aminoacyl-tRNA synthetase as a self-resistance mechanism. The structures of five closely related compounds of mixed polyketide─nonribosomal peptide origin were elucidated. Sequence analysis, mutagenesis and stable isotope feeding studies led to decoding of a plausible biosynthetic pathway for these natural products. The primary products, a trio of interconverting isomers designated vibriomycins A, B, and B', were found to be unusual allosteric inhibitors of bacterial threonyl-tRNA synthetases. Our study highlights the feasibility of discovering new anti-infective chemotypes via genome mining.