Identification of genes involved in the biosynthesis of the cytotoxic compound glidobactin from a soil bacterium.

Glidobactins (syn. cepafungins) are a family of structurally related cytotoxic compounds that were isolated from the soil bacterial strain K481-B101 (ATCC 53080; DSM 7029) originally assigned to Polyangium brachysporum and, independently, from an undefined species related to Burkholderia cepacia. Glidobactins are acylated tripeptide derivatives that contain a 12-membered ring structure consisting of the two unique non-proteinogenic amino acids erythro-4-hydroxy-l-lysine and 4(S)-amino-2(E)-pentenoic acid. Here we report the cloning and functional analysis of a gene cluster (glbA-glbH) involved in glidobactin synthesis from K481-B101, which according to its 16S rRNA sequence belongs to the Burkholderiales. The putative encoded proteins include a mixed non-ribosomal peptide/polyketide synthetase whose structure and architecture allowed to build a biosynthetic pathway model explaining the biosynthesis of the unique peptide part of glidobactins. Intriguingly, among the more than 600 bacterial strains whose genome sequence is currently available, homologous gene clusters were found in Burkholderia pseudomallei, the causing agent of melioidosis, and in the insect pathogen Photorhabdus luminescens, strongly suggesting that these organisms are capable to synthesize compounds similar to glidobactins. In addition, a glb gene cluster that was inactivated by transposon-mediated rearrangements was also present in Burkholderia mallei, a very close relative of B. pseudomallei and the causing agent of glanders in horse-like animals.