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Feature: Lifeline for antibiotic of last resort

Summer 2010

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An international team of scientists has uncovered how bacteria sense vancomycin, a mechanism that triggers resistance to this powerful antibiotic.

When other antibiotics fail, doctors turn to vancomycin - the only widespread effective therapy for the hospital superbug MRSA (methicillin-resistant Staphylococcus aureus).

But, despite keeping the drug in reserve to treat only serious, life threatening infections, vancomycin resistance has become a serious clinical problem, with growing prevalence in enterococci and more recently in the more virulent staphylococci, including the emergence of vancomycin-resistant MRSA in 2002.

"Vancomycin resistance is thankfully still rare in MRSA, but if it became more widespread we could risk edging backwards to the pre-antibiotic era," says Professor Mark Buttner from the John Innes Centre, an institute of BBSRC. "We need to have a back-up ready in case resistance becomes more common."

For 20 years scientists around the world have argued about whether bacteria sense the drug itself to trigger resistance or whether they sense the impact it has on the cell wall of bacteria. Buttner and his colleague Dr. Hee-Jeon Hong teamed up with biochemists at McMaster University in Canada to finally crack the problem.

"Vancomycin works in an unusual way and the mode of resistance in bacteria is also exceptional," explains Buttner.

Most antibiotics work by inhibiting a cell-wall building enzyme; vancomycin binds to the cell wall building blocks themselves, causing a weakness in the structure of the cell wall so the cell bursts and dies. Some scientists believed that bacteria detect the cell wall degradation to trigger resistance. Others argued that bacteria detect the presence of the drug directly.

The trans-Atlantic team studied the sensing mechanism in the harmless soil bacterium Streptomyces. They showed that bacteria detect vancomycin itself. They also conducted preliminary experiments that suggest the same mechanism exists in clinical pathogens. The results were published in Nature Chemical Biology.

McMaster's Professor Gerry Wright who led the study said, "If this mechanism is generally applicable to clinical strains, it could provide a simple biochemical assay for direct screening of new antibiotics and agents that can block induction of resistance."

"We have finally cracked the alarm system used by bacteria, and hopefully new antibiotics can be developed that don't set it off," says Buttner.

'A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor' was published online in Nature Chemical Biology, 11 April 2010, doi 10.1038/NCHEMBIO.350

John Innes, 100 years on

As part of a year-long programme of events to mark the centenary of genetics research by John Innes scientists, antibiotics research has been recognised as one of the top five most significant scientific achievements, alongside the development of John Innes Compost, semi-dwarfing wheat genes, advances in cereal breeding, and semi-leafless peas.

You can vote online for your favourite until 14 July at www.jic.ac.uk/centenary/vote.htm

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