Genomics-Guided Exploitation of Lipopeptide Diversity in Myxobacteria

Abstract

Analysis of 122 myxobacterial genome sequences suggested 16 strains as producers of the myxochromide lipopeptide family. Detailed sequence comparison of the respective mch biosynthetic gene clusters informed a genome-mining approach, ultimately leading to the discovery and chemical characterization of four novel myxochromide core types. The myxochromide megasynthetase is subject to evolutionary diversification, resulting in considerable structural diversity of biosynthesis products. The observed differences are due to the number, type, sequence, and configuration of the incorporated amino acids. The analysis revealed molecular details on how point mutations and recombination events led to structural diversity. It also gave insights into the evolutionary scenarios that have led to the emergence of mch clusters in different strains and genera of myxobacteria.

Metabolic and Biosynthetic Diversity in Marine Myxobacteria

“…The biosynthetic pathways of haliangicin [ 49 ] and haliamide [ 13 ] are encoded within the chromosome of H. ochraceum DSM 14365. Although not experimentally confirmed, M. xanthus HW-1 is most likely capable of myxochromide A biosynthesis, as it harbors the required core biosynthetic genes encoding proteins that exhibit average protein identity of 85% to the known producers [ 79 ]. The genome of M. xanthus HW-1 also encodes a DKxanthene biosynthetic gene cluster with a 65% to 85% average protein identity to the known producers S. aurantiaca DW4/3-1 [ 80 ] and M. xanthus DK1622 [ 81 ], respectively.…”

Synthetic biology approaches and combinatorial biosynthesis towards heterologous lipopeptide production

“…In a recent study on myxobacterial lipopeptide biosynthetic pathways we performed a comprehensive analysis of genetic changes in BGCs causing structural diversification of the lipopeptide products myxochromides, which seem to occur widespread among myxobacterial species. 24 Previous studies indicate a physiological role of myxochromides in the developmental life cycle of myxobacteria, 24 significant antimicrobial or cytotoxic activities were not detected in the applied testings. 25 , 26 Until now, five different types of myxochromides (A, B, C, D and S) differing in the amino acid composition of their peptide cores, and the corresponding BGCs ( mch gene clusters) have been identified ( Fig.…”

“…A short coding DNA sequence (CDS) located downstream of mchC was recently identified and designated as mchD , encoding a putative membrane protein of unknown function. 24 Phylogenetic analysis suggested the A-type mch cluster as the common ancestral gene cluster of the other known mch clusters. 24 The domain organizations in the megasynthetase subunits MchA and MchB among all pathways are identical, while significant differences have been found in MchC ( Fig.…”

“…1 ). 24 – 27 The mch clusters are around 30 kb in size and contain four co-transcriptional genes. The gene mchA encodes a type I iterative PKS module, which synthesizes the polyunsaturated lipid chains.…”

“…In addition to studies with the native myxochromide producer strains, proficient heterologous expression systems using Myxococcus xanthus , Pseudomonas putida and Corallococcus macrosporus as hosts could be established, 28 , 29 facilitating future efforts to further exploit this compound class. 24 …”