Penicillin‐binding protein 2a of methicillin‐resistant Staphylococcus aureus

Abstract

Summary High-level resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is due to expression of penicillin-binding protein 2a (PBP2a), a transpeptidase that catalyzes cell-wall crosslinking in the face of the challenge by β-lactam antibiotics. The activity of this protein is regulated by allostery at a site 60 Å distant from the active site, where crosslinking of cell wall takes place. This review discusses the state of knowledge on this important enzyme of cell-wall biosynthesis in MRSA.

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“…Expression by the bacteria of the mutant enzyme transpeptidase (mutant penicillin-binding protein -PBP2 enzyme) that has a reaction center practically inaccessible to the β-lactam antibiotics but, on the other hand, perfectly capable of catalyzing the crosslinking reaction in the course of peptidoglycan synthesis, serves as another way of bacterial resistance to β-lactam antibiotics [41]. It was discovered that in order to catalyze the crosslinking of peptidoglycan the active center of the enzyme should undergo conformational change.…”

“…It was discovered that in order to catalyze the crosslinking of peptidoglycan the active center of the enzyme should undergo conformational change. This conformational change is probably triggered by the interaction of the corresponding peptidoglycan fragments with the allosteric site of this enzyme [41]. Then, it was shown that some β-lactams like ceftaroline are able to interact with the allosteric site of the enzyme leading to the conformational change -opening of its active site -that enables the second molecule of ceftaroline to react with the enzyme active site, thereby finishing the enzyme inactivation [41,42].…”

“…This conformational change is probably triggered by the interaction of the corresponding peptidoglycan fragments with the allosteric site of this enzyme [41]. Then, it was shown that some β-lactams like ceftaroline are able to interact with the allosteric site of the enzyme leading to the conformational change -opening of its active site -that enables the second molecule of ceftaroline to react with the enzyme active site, thereby finishing the enzyme inactivation [41,42]. Fishovitz et al reported that the triggering of the allosteric cite of PBP2 enzyme by one β-lactam antibiotic enables another β-lactam drug to interact with the active cite of that protein.…”

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“…This physico-chemical alteration decreases the affinity of the drug for the site and causes loss of antimicrobial activity. As an example of this, mechanism of action is seen in the literature methicillin resistant Staphylococcus aureus, and penicillin resistant Streptococcus pneumoniae [27,28]. the expulsion of the antibiotics by cell, contributing to an inadequate concentration of the drug and consequently, ineffective action.…”

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“…β-lactam antibiotics bind to penicillin binding proteins [20] however, the Methicillin Resistant S. aureus (MRSA) strain has the SCCmec (Staphylococcal Cassette Chromosome) and the mecA gene that encodes the mutation of the penicillin binding protein, avoiding binding to β-lactams antibiotics [29]. Therefore, MRSA is resistant to all penicillins, cephalosporins and carbapenems [30]. Another example is the fluoroquinolones resistance, which occurs through mutations on topoisomerases that are essential for DNA replication, and the methylation of the ribosome [31].…”