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Biological Chemistry

Shape-Shifting Antibiotic Resistance

In an unprecedented mechanism, MRSA’s protein mutants are found to disrupt allosteric changes that leave the bacterium vulnerable to antibiotics

by Elizabeth K. Wilson
July 7, 2014 | APPEARED IN VOLUME 92, ISSUE 27

The antibiotic ceftaroline was approved by FDA in late 2010 to battle the problematic methicillin-resistant Staphylococcus aureus (MRSA) bacterium. But studies have shown that the ever-mutating organism has already developed resistance to this antibiotic. A team led by Shahriar Mobashery of the University of Notre Dame and Juan A. Hermoso of the Spanish National Research Council now shows that a hitherto unrecognized mechanism—the prevention of allosteric motions that allow the antibiotic to bind to a bacterial protein—is responsible for this resistance (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5030657). β-Lactam antibiotics such as penicillins and cephalosporins kill bacteria by disrupting cell-wall biosynthesis. However, mutations in the active site of the target protein prevent the antibiotic from binding. Ceftaroline’s action involves two steps: First, a ceftaroline molecule causes an allosteric change in the target protein; then this change makes the protein’s active site available for binding by a second molecule. With kinetic studies and X-ray crystallography, the researchers show that mutations in the MRSA protein now prevent the first ceftaroline molecule from causing those crucial conformational changes. Because of the importance of allostery in many biological systems, the authors argue that such allo­steric mechanisms may also be at work in other antibiotic-resistant systems.

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