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MRSA’s killing potential explained, providing a new drug target to halt the superbug

Since it first arose more than 50 years ago, the methicillin-resistant staph infection known as MRSA has ravaged hospital wards around the globe, causing untreatable, often lethal, infections in people already weakened by disease. As with most cases of antibiotic resistance, the rise of the first MRSA bacteria was the fault of humans. The Staphylococcus aureus bacterium, which causes everything from respiratory infections to meningitis, mutated to become resistant to all the first-line drugs used to treat it—first penicillin, and later methicillin and other drugs known as beta-lactams.

But the story doesn’t end there. Since 1959, the drug-resistant superbugs have taken on many guises, evolving into five major lineages worldwide, each with slightly different genes that make the pathogens particularly deadly. Yet, how each strain’s killing power arose largely remains a mystery. Now, a paper published today in Nature Medicine takes a step toward explaining the killing mechanism of one particular strain from China. By sorting through a decade’s worth of superbugs isolated from Chinese hospitals, the authors have identified a resistance gene encoded by a mobile genetic element that helps S. aureus multiply in the noses, throats and lungs of susceptible patients.

“This is very exciting,” says study author Michael Otto, chief of the Pathogen Molecular Genetics Section at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “This gene is a critical determinant how dangerous MRSA is to patients.”

The gene, called sasX, caught Otto’s attention because it was present in the genome of a major Chinese strain of MRSA—first identified in the late 1970s and eventually sequenced in 2010—but its function was unknown. Working with Min Li, a former postdoc now working at Fudan University in Shanghai, Otto searched for the presence of the sasX gene in more than 800 samples of MRSA taken from patients in three different Chinese hospitals over a nine year period. They found that sasX, which has not been found in any other strains of S. aureus across the globe, had been steadily spreading among subtypes of the Chinese bacterial strain, growing from 19% of confirmed staph cases in 2003 to 31% last year. “Clearly sasX is spreading quickly, but we still didn’t know whether the gene was responsible for causing diseases in patients,” explains Otto.

To find out, the researchers exposed mice to versions of MRSA with and without sasX to see whether the bacteria successfully latched onto the cells in the animals’ nasal passages, a telltale sign of the bug’s colonization ability and pathogenecity. In mice exposed to MRSA with sasX, the bacteria invaded the nasal passages and multiplied rapidly, but in animals exposed to MRSA lacking the gene, the bacteria failed to adhere and replicate.

Although the findings are still preliminary, Otto says that sasX could be a promising therapeutic target. Potentially, the protein encoded by sasX, which is expressed on the surface of the bacterium to help it grab on to the mammalian epithelial cell lining, could be hit by a new class of antibiotics or MRSA vaccines.

“This has enormous implications as a target for therapies for MRSA, and not just in China,” says Marco Salemi, an evolutionary biologist at the University of Florida in Gainsville who studies the predominant US strain of MRSA. “It will be very interesting to see whether [the US strain] has anything like sasX in its genome.”

For more on the barriers to MRSA treatment and the history of MRSA in China, CLICK HERE to listen to a special preview of our interview with Michael Otto in the upcoming May edition of the Nature Medicine podcast.

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