Mechanisms of heteroresistance in methicillin-resistant Staphylococcus aureus

Abstract

Characteristic for methicillin-resistant (Mcr) staphylococci is the heterogeneous expression of the intrinsic methicillin resistance. The majority of the cells express resistance to low concentrations of methicillin, and a minority of the cells express resistance to much higher concentrations. We show here (i) progeny. Transductants derived from the formerly highly resistant cured strain became resistant to high concentrations of methicillin, whereas transductants derived from the original parent strain were resistant to lower concentrations of methicillin and showed the typical heterogeneous resistance. We deduced therefrom that the high-level resistance expressed by the minority of the population of Mcr S. aureus was due to a chromosomal mutation(s) (chr*) involving neither mecA nor the additional 30 kb of mec-associated DNA. Moreover, we could show that this postulated mutation chr* was not linked to the femAB operon, which is known to affect methicillin resistance levels.Clinical isolates of methicillin-resistant (Mcr) Staphylococcus aureus contain the methicillin resistance determinant mec, which confers an intrinsic resistance to all P-lactam antibiotics.The mec determinant is located on additional DNA of unknown origin and nature and integrates into a specific site in the chromosome of S. aureus (14). The mec determinant codes for mecA, the structural gene for low-affinity penicillin-binding protein (PBP2' or PBP2a). This PBP2' adds to the existing PBPs of the cell and is the biochemical correlate of methicillin resistance (13,18,28). Some strains contain mecRI-mecI, which code for elements regulating mecA transcription (23,26,27). Only a small part of the remaining 30 kb of DNA associated with mecA (3) has been characterized. It

Spontaneous Deletion of the Methicillin Resistance Determinant, mecA , Partially Compensates for the Fitness Cost Associated with High-Level Vancomycin Resistance in Staphylococcus aureus

“…The conversion from heterotypic to homotypic methicillin resistance is not well understood. However, it is has been shown that the conversion is due to mutational events occurring outside of SCCmec and is not a result of increased mecA expression (20,38). Further investigation into the mechanism of heterotypic-homotypic conversion may shed light on the cause of the mecA-associated fitness cost in these strains.…”

Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus in Finland

“…The expression of methicillin resistance varies among strains (107, 166,234). Strains with intact mecImecR1 regulon are phenotypically methicillin sensitive, since mecA is effectively repressed by MecI (260).…”

“…This type of resistance is achieved by exposing strains with intact mecA regulon to a high methicillin concentration. The expression of eagle-type resistance and the conversion of heterogeneous resistance to homogeneous resistance are thought to result from the same genetic factor independent of SCCmec and fem factors (134,234).…”

Hetero-resistance: an under-recognised confounder in diagnosis and therapy?

“…The genes responsible for this conversion to high-level resistance have not yet been identi®ed, but it has been shown that the conversion must be due to chromosomal mutation(s) that are not related to mecA [1,2].…”

“…Expression of this protein causes strain-speci®c, variable resistance from borderline to elevated basal resistance to methicillin and all other â-lactam antibiotics. It can be induced by increased osmolarity, lowered temperature and other factors [1].…”