Specific Mechanism that Triggers Resistance to Vancomycin Discovered

Resistance to the antibiotic vancomycin requires expression of vanH, vanA, and vanX under control of several other mechanisms, according to new research from McMaster University.

Researchers at McMaster University, in collaboration with colleagues at the John Innes Centre and the University of Cambridge, have identified the specific mechanism that triggers resistance to vancomycin, the antibiotic used when all other treatment options have failed.

Writing in the April 11 online edition of Nature: Chemical Biology, lead author Kalinka Koteva and colleagues explained that “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 team used a synthesized vancomycin photoaffinity probe to 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.”

Scientists did not expect resistance problems to arise with vancomycin so quickly.

"For years, it was thought that resistance would be slow to emerge, since vancomycin works in an unusual way,” explained Gerry Wright, biochemistry and biomedical sciences professor, McMaster, and scientific director, Institute for Infectious Disease Research. “But with the widespread use of the drug to treat infections caused by the hospital superbug MRSA, it has become a serious clinical problem."

The study, performed in the harmless soil bacteria Streptomyces coelicolor, revealed that bacteria detect vancomycin itself, and preliminary experiments show that the same mechanisms involved in vancomycin resistance also exist in disease-causing bacteria.

"We have finally cracked the alarm system used by bacteria, and hopefully new antibiotics can be developed that don’t set it off," said Mark Buttner, a study collaborator and senior scientist at the John Innes Centre.

Marc Ouellette, scientific director of the Institute of Infection and Immunity at the Canadian Institutes for Health Research (CIHR), explained that this study “lays the groundwork for developing new therapies to prevent and treat antibiotic-resistant infections."