Washington: A new study has revealed the mechanistic basis for how the methicillin-resistant Staphylococcus aureus (MRSA) bacterium became such a difficult pathogen over the previous 50 years, in which time it spread rapidly across the world.
The study by researchers at university of Notre Dame and their collaborators in Spain showed how MRSA regulates the critical crosslinking of its cell wall in the face of beta-lactam antibiotics.
Modern strains of MRSA have become broadly resistant to antibiotics, including beta-lactam antibiotics, such as penicillins.
In their report, the researchers disclose the discovery of an allosteric domain in the X-ray structure of the penicillin binding protein 2a of MRSA, the enzyme that carries out the crosslinking reaction.
The researchers documented that an allosteric trigger by a fragment of the cell wall at a distance of 60 Angstroms (6 nanometers) activates a set of conformational changes that culminates in the opening of the active site from a closed conformation, enabling catalysis for the physiological role of the enzyme.
They also documented that the new beta-lactam antibiotic ceftaroline, recently approved by the Food and Drug Administration, is able to bind to the allosteric domain and trigger the same allosteric opening of the active site. This subversion of the allosteric control allows another molecule of ceftaroline to access the active site, which inhibits the function of the enzyme, leading to cell death by MRSA.
The study is published in the Proceedings of the National Academy of Sciences.
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