S12: MbtH homologs as beacons for mining and expression of antibiotics produced by NRPS pathways

Mycobacterium tuberculosis encodes mycobactin, a peptide siderophore that is biosynthesized by a nonribosomal peptide synthetase (NRPS) mechanism. Within the mycobactin biosynthetic gene cluster is a small gene that encodes a 71 amino acid protein MbtH. Many other NRPS gene clusters harbor mbtH homologs, and recent genetic, biochemical and structural studies have begun to shed light on the function(s) of these proteins. In some cases, MbtH-like proteins are required for biosynthesis of their cognate peptides, and non-cognate MbtH-like proteins have been shown to partially substitute for cognate Mbt-like proteins. Biochemical studies have revealed that certain MbtH-like proteins participate in tight binding to small NRPS proteins containing adenylation (A) domains where they stimulate adenylation reactions. Importantly, mbtH homologs are present in gene clusters that encode clinically important antibiotics, including vancomycin, teicoplanin, daptomycin, pristinamycin I, and capreomycin, and as such may serve a beacons for the identification of potentially useful novel antibiotic pathways in genome sequencing projects. In this talk, I discuss the distribution of mbtH-like genes in microbes and point out the potential value of surveying multiple actinomycte genomes for multiple, diverse mbtH genes as a predictors of productive genera and species for focused DNA sequencing to discover new peptide antibiotics.