title: Activation for catalysis of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus by bacterial cell wall.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) has acquired a unique penicillin-binding protein (PBP), PBP 2a, which has rendered the organism resistant to the action of all available beta-lactam antibiotics. The X-ray structure of PBP 2a shows the active site in a closed conformation, consistent with resistance to inhibition by beta-lactam antibiotics. However, it is known that PBP 2a avidly cross-links the S. aureus cell wall, which is its physiological function. It is shown herein that synthetic fragments of the bacterial cell wall bind in a saturable manner to PBP 2a and cause a conformational change in the protein that makes the active site more accessible to binding to a beta-lactam antibiotic. These observations and measurements point to a novel strategy by nature to keep the active site of PBP 2a sheltered from the inhibitory activity of the antibiotics, yet it becomes available to the polymeric cell wall by a requisite conformational change for the critical cell wall cross-linking reaction.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Fuda
authors.forename: Dusan
authors.initials: D
authors.lastname: Hesek
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Morio
authors.forename: Thomas
authors.initials: T
authors.lastname: Nowak
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
mesh_terms: D002384:Catalysis; D002473:Cell Wall / Q000378:metabolism; D002511:Cephalosporins / Q000378:metabolism / Q000494:pharmacology*; D002942:Circular Dichroism; D016106:Methicillin Resistance; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010457:Peptidoglycan / Q000378:metabolism / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D010446:Peptide Fragments; D010457:Peptidoglycan; C021720:nitrocefin