Bromobalhimycin and Chlorobromobalhimycins—Illuminating the Potential of Halogenases in Glycopeptide Antibiotic Biosyntheses

Abstract

Can bromine beat bacteria? By varying the amounts of chloride and bromide salts in fermentation culture media, we have generated novel sets of vancomycin‐type glycopeptides with bromine substitution. This study extends the sequence of substituents at the aglycon moiety of balhimycin from H through F and Cl to Br (see scheme) and opens up possibilites for the investigation of substituent effects upon the activity of glycopeptide antibiotics.

Dichlorination of a pyrrolyl-S-carrier protein by FADH 2 -dependent halogenase PltA during pyoluteorin biosynthesis

“…For example, the deschloro analog of the antibiotic clorobiocin was 8-fold less active against Bacillus subtilis (5). Removal of the chlorine atoms from balhimycin, a glycopeptide antibiotic, resulted in an 8-to 16-fold reduction in the activity against a variety of pathogenic bacteria, whereas bromobalhimycin in which chlorine is replaced by bromine groups was twice as active against Enterococcus faecium but 8-fold less active against Staphylococcus aureus (10). Characterization of the chlorination step, including timing, substrate tolerance, regiospecificity, and mechanism, is critical for unlocking the potential for natural product diversification for these biologically important compounds.…”

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

“…Halogenation often has significant consequences for the bioactivity of these natural products. For instance, the deschloro analog of the antibiotic balhimycin was 8-to 16-fold less active against a variety of pathogenic bacteria (11).…”

Highlighting the role of the chlorine substituents in the glycopeptide antibiotic balhimycin for chiral recognition in capillary electrophoresis

“…1) were prepared by fermentation and were purified by preparative LC [20,[24][25][26]. All dansyl derivatives of D,L and L-amino acids (i.e.…”