Tri-chlorination of a teicoplanin type glycopeptide antibiotic by the halogenase StaI evades resistance [Mechanisms of Resistance]

Glycopeptide antibiotics (GPAs) include clinically important drugs used for the treatment of infections caused by Gram positive pathogens. These antibiotics are specialized metabolites produced by several genera of actinomycetes bacteria. While many GPAs are highly chemically modified, A47934 is a relatively unadorned GPA lacking sugar or acyl modifications, common to other members of the class, but which is chlorinated at three distinct sites. The biosynthesis of A47934 is encoded by a 68 kb gene cluster in Streptomyces toyocaensis NRRL 15009. The cluster includes all the necessary genes for the synthesis of A47934 including two predicted halogenase genes, staI and staK. In this study, we report that only one of the halogenase genes, staI, is necessary and essential for A47934 biosynthesis. Chlorination of the A47934 scaffold is important for antibiotic activity as assessed by binding affinity for the target N-acyl-D-Ala-D-Ala. Surprisingly, chlorination is also vital to avoid activation of enterococcal and Streptomyces VanB-type GPA resistance through induction of resistance genes. Phenotypic assays showed stronger induction of GPA resistance by the dechlorinated compared to the chlorinated GPA. Correspondingly, the relative expression of enterococcal vanA resistance gene was shown to be increased by the dechlorinated compared to the chlorinated compound. These results provide insight into the biosynthesis of GPAs and the biological function of GPA chlorination for this medically important class of antibiotic.

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