PBP2a: The Means for β‐lactam Resistance

Abstract

Methicillin‐resistant Staphylococcus aureus (MRSA) is a scourge of modern hospitals causing significant morbidity and mortality. MRSA is a formidable threat due to its resistance to β‐lactam antibiotics. β‐lactams function in normal S. aureus strains by inhibiting the action of penicillin‐binding‐protein (PBP), which synthesizes the cell wall by forming peptide bonds between short segments of peptidoglycan. β‐lactams acylate the Ser 403 active site of PBP, causing the substrate to be unable to attach to it, thus inhibiting the enzyme and effectively initiating death. β‐lactam resistance in MRSA is due to mecA, which encodes a variant of PBP known as PBP2a. At normally lethal β‐lactam concentrations, PBP2a is resistant to the antibiotics due to its lower affinity to β‐lactams, which decreases the rate of formation of the acyl‐PBP2a intermediate. This reaction is also inefficient because the active site has to undergo conformational changes for acylation to happen; these changes do not occur in PBP2a. The Marshfield SMART Team (Students Modeling A Research Topic) designed a 3D model of the transpeptidase domain of PBP2a to understand the structural basis of β‐lactam resistance. Using this model, one can design newer antimicrobials with improved binding affinity between the drug molecule and the active site of PBP2a. Supported by grants from the Marshfield Clinic and School District of Marshfield and NIH‐SEPA