A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor

Inducible resistance to the glycopeptide antibiotic vancomycin requires expression of vanH, vanA and vanX, controlled by a two-component regulatory system consisting of a receptor histidine kinase, VanS, and a response regulator, VanR. The identity of the VanS receptor ligand has been debated. Using a synthesized vancomycin photoaffinity probe, we show that vancomycin directly binds Streptomyces coelicolor VanS (VanSsc) and this binding is correlated with resistance and required for vanH, vanA and vanX gene expression. The emergence of resistance to the glycopeptide antibiotic vancomycin (1) has had an enormous impact on the health care sector. Vancomycin binds to the acyl-D-alanyl-D-alanine (acyl-D-Ala-D-Ala) side chain of the muramyl pentapeptide component of bacterial peptidoglycan, thereby interfering with cell wall biosynthesis. The near ubiquity of the D-Ala-D-Ala terminus in bacterial peptidoglycan and the fact that the antibiotic binds to a substrate rather than an enzyme (which could be susceptible to mutation) provided some confidence to the infectious disease community that vancomycin resistance would be slow to emerge. Nevertheless, glycopeptide resistance did indeed emerge in pathogenic enterococci in 1988 (ref. 1). This consequence followed a significant increase in use of oral vancomycin and its lipoglycopeptide analog teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), along with the widespread use of an analog (avoparcin) in animal feed. Twenty years later, vancomycin resistance has become a serious clinical problem, with a growing prevalence in enterococci and more recently in the more virulent staphylococci 2