Abstract
β-lactam antibiotics target penicillin-binding proteins (PBPs) preventing peptidoglycan synthesis and this inhibition is circumvented in methicillin resistant Staphylococcus aureus (MRSA) strains through the expression of an additional PBP, named PBP2A. This enzyme is encoded by the mecA gene located within the Staphylococcal Chromosome Cassette mec (SCCmec) mobile genetic element, of which there are 12 types described to date. Previous investigations aimed at analysing the synergistic activity of two β-lactams, oxacillin and cefoxitin, found that SCCmec type IV community-acquired MRSA strains exhibited increased susceptibility to oxacillin in the presence of cefoxitin, while hospital-acquired MRSA strains were unaffected. However, it is not clear if these differences in β-lactam resistance are indeed a consequence of the presence of the different SCCmec types. To address this question, we have exchanged the SCCmec type I in COL (HA-MRSA) for the SCCmec type IV from MW2 (CA-MRSA). This exchange did not decrease the resistance of COL against oxacillin and cefoxitin, as observed in MW2, indicating that genetic features residing outside of the SCCmec element are likely to be responsible for the discrepancy in oxacillin and cefoxitin synergy against these MRSA strains.
Highlights
The key determinant of β-lactam resistance is the expression of PBP2A, an additional penicillin-binding proteins (PBPs) that has low affinity for β-lactams, thereby maintaining transpeptidation activity in the presence of otherwise lethal concentrations of these antibiotics[4]
We aimed to analyse the effects of exchanging the Staphylococcal Chromosome Cassette mec (SCCmec) type I of COL with type IV of MW2, in order to determine whether the resistance of HA-methicillin resistant S. aureus (MRSA) strain COL to the synergistic action of oxacillin and cefoxitin was dependent on the type of SCCmec
Since the acquisition of type IV SCCmec could confer a low level of oxacillin resistance, selection was performed with 4 μg/ ml oxacillin
Summary
The key determinant of β-lactam resistance is the expression of PBP2A, an additional PBP that has low affinity for β-lactams, thereby maintaining transpeptidation activity in the presence of otherwise lethal concentrations of these antibiotics[4]. The increase in MRSA incidence has led to a need for alternative therapies, the focus of which has been the identification of new antibiotics with novel killing mechanisms, and the study of synergistic activity of currently available drugs One such example is the use of two β–lactams, oxacillin and cefoxitin, which have highest affinity for different PBPs (PBP1/PBP2, and PBP4, respectively)[19]. Genetic inactivation of pbpD encoding PBP4 was found to decrease resistance to oxacillin[19] This effect is not observed in HA-MRSA SCCmec type I strain COL, and further blind testing of clinical isolates found that all tested type IV SCCmec strains demonstrated a synergistic oxacillin and cefoxitin inhibitory effect, while HA-MRSA strains did not[19, 20]. The results shown here indicate that the genetic differences between SCCmec type I and type IV do not significantly alter the resistance level or the morphological response of COL to the challenge of these β-lactams, indicating that there are additional key genetic factors involved
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