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Staying a step ahead of staph
Antibiotic resistance is catching up with even the most powerful drugs. How Rockefeller scientists are fighting back.
It started with a 40-year-old Michigan man with diabetes, heart disease and kidney failure.
He’d had a bad year. Because of vascular disease, he had sores on his feet that wouldn’t heal, and two months earlier gangrene had developed on a toe, requiring amputation. He’d been on a cocktail of antibiotics including one called methicillin, a relative of penicillin, and vancomycin, which for 40 years has been the drug of last resort for fighting stubborn bacterial infections that resist other antibiotics.
In June of 2002, the Michigan man developed an infection at the exit site of the catheter used for his kidney dialysis treatments. Cultures taken from the site showed that the responsible microbe was Staphylococcus aureus, the bacterium underlying as many as 2 million infections and 80,000 deaths each year in the U.S. — and that it was resistant to both methicillin and vancomycin.
It was the first time in medical history that staph had successfully fought off the antibiotics of last resort.
Less than four months later, bacteriologists’ worst fears were confirmed: a culture from a separate patient in Pennsylvania also tested positive for vancomycin resistant S. aureus. In both the Michigan and Pennsylvania patients, the infections are believed to have been caused by staph bacteria that had acquired a gene complex called vanA from vancomycin-resistant Enterococcus faecalis bacteria that were also present at the sites of the infections.
Now, in Alexander Tomasz’ Rockefeller University lab, scientists are beginning to piece together the molecular picture of how this strain of staph bacteria resists both drugs.
Both methicillin and vancomycin work by destroying the bacterium’s cell wall, but they do so in different ways. In the case of methicillin, the drug inactivates four different proteins — called penicillin-binding proteins — that the bacterium needs to construct its cell wall; to survive methicillin, staph acquired a gene called mecA, which produces a new penicillin-binding protein that takes over cell wall construction when the bacterium’s apparatus becomes paralyzed. Vancomycin, on the other hand, physically traps the molecular building blocks that penicillin-binding proteins use to assemble the cell wall; to survive vancomycin, staph acquired a gene called vanA, which produces an abnormal cell wall precursor that the drug doesn’t recognize.
“Both resistance mechanisms are targeted on the bacterial cell wall and each seems to be custom designed to match precisely the mode of action of the antibiotics,” says Tomasz.
To search for new weaknesses, Tomasz and Anatoly Severin, senior research associate, working with colleagues at the U.S. Centers for Disease Control in Atlanta, examined a strain of S. aureus with resistance levels to vancomycin close to 1000 times higher than normal. They made two encouraging discoveries.
First, they noticed that using the two drugs in combination was extremely effective, even at relatively low doses. The new penicillin-binding protein produced by staph resistant to methicillin, it turns out, is unable to utilize the abnormal cell wall precursor produced by staph resistant to vancomycin.
“The mechanism is antagonistic,” says Tomasz, head of the Laboratory of Microbiology. “If you challenge this bacterium with either vancomycin or methicillin, it is very resistant. However, if you combine the two antibiotics, this resistance collapses.” That finding — that both drugs together are still effective — is encouraging news for doctors who soon may find themselves without a single drug capable of killing staph infections.
Secondly, the Rockefeller scientists showed that the structure of the cell wall produced from the abnormal cell wall precursor has several abnormalities itself — abnormalities that may make the resistant bacteria less likely to spread, at least in patients with healthy immune systems.
“What we hope is that, at least for the time being, the vancomycin resistant S. aureus has a price to pay for its victory against vancomycin by surrendering some of the skills that make it such a dangerous pathogen,” Tomasz says.

February 27, 2004



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