耐甲氧西林金葡菌耐药性的关键

University of Notre Dame¹ researchers Shahriar Mobashery and Mayland Chang and their collaborators in Spain have published research results this week that show how methicillin-resistant² Staphylococcus aureus (MRSA) regulates the critical crosslinking of its cell wall in the face of beta-lactam（内酰胺） antibiotics⁴. The work, published in the Proceedings⁵ of the National Academy of Sciences, reveals the mechanistic basis for how the MRSA bacterium⁶ became such a difficult pathogen over the previous 50 years, in which time it spread rapidly across the world. Modern strains of MRSA have become broadly resistant to antibiotics, including beta-lactam antibiotics, such as penicillins（青霉素）. In their report, the researchers disclose the discovery of an allosteric（变构的） domain⁸ in the X-ray structure of the penicillin⁷ binding¹⁰ protein 2a of MRSA, the enzyme¹¹ that carries out the crosslinking reaction. (An allosteric site is a place on the protein where its activity is regulated by the binding of another molecule¹².)

 

Mobashery, Chang and Juan Hermoso at CSIC, the Spanish Research Council, document that an allosteric trigger by a fragment of the cell wall at a distance of 60 Ångstroms (6 nanometers) activates¹³ a set of conformational changes that culminates¹⁴ in the opening of the active site from a closed conformation, enabling catalysis for the physiological¹⁵ role of the enzyme.

 

They also document that the new beta-lactam antibiotic³ ceftaroline, recently approved by the Food and Drug Administration, is able to bind⁹ to the allosteric domain and trigger the same allosteric opening of the active site. This subversion¹⁶ of the allosteric control allows another molecule of ceftaroline to access the active site, which inhibits¹⁷ the function of the enzyme, leading to cell death by MRSA. This mechanism¹⁸ of action for the antibiotic is unprecedented¹⁹ and offers important insights for design of future drugs to combat MRSA.

 

MRSA has been a difficult hospital pathogen to control and has emerged in the broader community in the past several years, especially in such places as prisons, locker²⁰ rooms and nurseries. In the United States alone, the disease infects about 100,000 people and claims the lives of nearly 20,000 people annually²¹.

分享到：