Genetic insights into the mechanism of teicoplanin self-resistance in Actinoplanes teichomyceticus

Abstract

Actinoplanes teichomyceticus NRRL B-16726 is the only known producer of the clinically important glycopeptide antibiotic teicoplanin. The producing strain is highly self-resistant to teicoplanin. Although the biosynthesis of teicoplanin has been investigated, much of our understanding of self-resistance in the producing strain is based on the extrapolation of existing data about glycopeptide resistance (mediated by the expression of vanRS-vanHAX genes) in other actinomycetes and cocci. The organization of the operons carrying putative van orthologues in A. teichomyceticus differs from known precedents, further adding up to the uncertainty about teicoplanin self-resistance mechanisms. Here, we determined operon structure of the teicoplanin resistance genes in A. teichomyceticus. Although Tei15* is necessary to activate teicoplanin biosynthetic genes, the expression of van orthologues was shown to be independent of Tei15*. We further showed that tei7 promoter driving the expression of vanHAX orthologues is dependent on Tei2 (VanR). Finally, we demonstrate the utility of the tei2 promoter as a new tool to achieve strong constitutive expression in A. teichomyceticus.