Binding of  -Lactam Antibiotics to Penicillin-Binding Proteins in Methicillin-Resistant Staphylococcus aureus

Abstract

Binding affinity of penicillin-binding proteins (PBP) of Staphylococcus aureus for several beta-lactam antibiotics was examined in a methicillin-susceptible strain and in two methicillin-resistant strains, one heterogeneous and one homogeneous, to determine relationships between PBP binding and expression of resistance. PBPs 1-4 had similar affinities in all three strains. PBP 2a affinities were similar in both resistant strains. For the susceptible strain and for the susceptible subpopulation of cells in the heterogeneous strain, growth inhibition correlated with binding to PBPs 1-3, suggesting that these PBPs mediate susceptibility in both. For resistant cells, growth inhibition correlated only with binding to PBP 2a, suggesting that this is the target in resistant cells. Determination of binding affinity for PBP 2a or the concentration that inhibits growth of the most resistant subpopulation of cells should be included in evaluation of beta-lactam antibiotics for potential activity against methicillin-resistant strains of S. aureus.

Methicillin-Resistant Staphylococcus aureus : Comparison of Susceptibility Testing Methods and Analysis of mecA -Positive Susceptible Strains

“…While a few clinical isolates of MRSA express homogeneous oxacillin resistance (i.e., Ն1 in 10 2 cells express high-level resistance), the majority of isolates have heterogeneous drug resistance (heteroresistance) (5,6,13). Phenotypic expression of resistance can vary depending on the growth conditions (e.g., the temperature or osmolarity of the medium), making susceptibility testing of MRSA by standard microbiological methods potentially problematic (5).…”

Public transport: a large scale fomite of methicillin-resistant Staphylococcus aureus

“…3 In our study 18 Staphylococcus aureus showed the MIC of 4 g/ml suggesting high incidence of MRSA from non-clinical specimens. Of the total Staphylococcus aureus isolated, 87.5% were resistant to multiple class of drugs.…”

“…1,3 MRSA is a major cause of morbidity and mortality both in healthcare settings and in healthy individuals in the last two decades. The global emergence and spread of MRSA harbouring multi-resistance genes limits the effectiveness of therapeutic options for staphylococcal infections and worsens their clinical outcomes.…”

“…The most important is the production of an altered penicillin-binding protein (PBP). 3 Methicillin-resistant Staphylococcus aureus (MRSA) is an important public health threat in India, with significant disease burden. 4 Of particular concern are the growing number of cases that have origins in the community (CA-MRSA); these infections often affect individuals without underlying risk factors for disease.…”

Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in Finland

“…PBP2a has probably evolved by recombination of a penicillinase gene and a PBP gene similar to PBP2 and PBP3 of Escherichia coli (255). PBP2a has an unusually low binding affinity for all beta-lactam antibiotics, substituting the native PBPs and allowing continuous cell wall assembly (36,228). However, the production of PBP2a alone is not sufficient for optimal expression of methicillin resistance (216).…”