Genome-wide identification and characterization of macrolide glycosyltransferases from a marine-derived Bacillus strain and their phylogenetic distribution.

Clarifying glycosyltrasferases (GTs) function is of significance for the development of GT inhibitors as drugs, and the use of GTs to glycodiversify small molecules in the search of drug leads. While many Actinomyces natural-product GTs had been functionally characterized, our understanding towards Bacillus natural-product GTs is so far very limited. Herein, genome-wide identification of macrolide GT genes from marine-derived Bacillus methylotrophicus B-9987 revealed the presence of three macrolide GT genes bmmGT1-3. While bmmGT1 was previously revealed to be involved in the biosynthesis of trans-acyltransferase (AT) polyketides compounds macrolactins (MLNs) and bacillaenes (BAEs), the functions of bmmGT2 and bmmGT3 were probed, demonstrating that they are capable to biochemically catalyze glycosylation of MLNs and BAEs as well but interestingly with different regioselectivity, affording four new MLNs analogs. Notably, further genome mining revealed that the orthologs of these three macrolide GT genes showed a regular distribution in the subtilis- and the cereus-clade Bacillus strains; interestingly, bmmGT1 orthologs only occurred in the subtilis-clade Bacillus, and they were also found in the genomes of Streptomyces strains, suggesting their close phylogenetic relationship. These results provide the first significant insight into the important roles of Bacillus macrolide GTs in the biology of the species.