A chlorinated diketopiperazine antibiotic targets Mycobacterium tuberculosis

We describe a novel macrocyclic peptide, speirobactin, produced by Photorhabdus temperata that selectively kills Mycobacterium tuberculosis. A nonribosomal peptide synthase containing two linear modules codes for the synthesis of speirobactin. The biosynthetic operon contains a pentapeptide-repeat protein as a resistance gene. Genomic analysis of speirobactin-resistant mutants of M. tuberculosis led to the identification of DNA gyrase as the molecular target. The mutations were recreated and show that DNA gyrase is the only target. Transcriptome analysis of M. tuberculosis treated with antibiotics shows that speirobactin clusters close to fluoroquinolones, supporting its action against the DNA gyrase.