The mechanism of the β-lactam antibacterials is the functionally irreversible acylation of the enzymes that catalyze the cross-linking steps in the biosynthesis of their peptidoglycan cell wall. The Gram-positive pathogen Staphylococcus aureus uses one primary resistance mechanism based on an enzyme, called penicillin-binding protein 2a (PBP2a), which is involved in this biosynthetic pathway being able to discriminate effectively against the β-lactam antibiotics as potential inhibitors, and in favor of the peptidoglycan substrate. The basis for this discrimination is an allosteric site, distal from the active site, that when properly occupied concomitantly opens the gatekeeper residues within the active site and realigns the conformation of key residues to permit catalysis. Throughout a combination of different techniques (X-ray crystallography and computational analysis by molecular dynamics and quantum mechanics), our results provide critical information about the regulation mechanism of PBP2a, a key protein in the primary resistance mechanism against antibiotics, giving us detailed information about the structural basis of communication between the allosteric and catalytic sites. Furthermore, this study reveals how β-lactam antibiotics mimicry the peptidoglycan substrates, as foundational to the mechanistic understanding of emerging PBP2a resistance mutations. This is part of a collaborative effort between the IQFR and the Univ. of Notre Dame (Indiana, USA).

Mahasenan, K.; Molina, R.; Bouley, R.; Batuecas, M.; Fisher, J.; Hermoso, J.A.; Chang, M. and Mobashery*, S. “Conformational dynamics in penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus, allosteric communication network and enablement of catalysis”. J. Am. Chem. Soc. (2017).
DOI: 10.1021/jacs.6b12565