Mechanism of Resistance in Methicillin-Resistant Staphylococcus aureus (MRSA)
The primary mechanism of resistance in MRSA is the acquisition of the mecA gene, which encodes for penicillin-binding protein 2a (PBP2a), a protein with significantly lower affinity for β-lactam antibiotics, allowing cell wall biosynthesis to continue even in the presence of typically inhibitory concentrations of these antibiotics. 1
Primary Resistance Mechanism
mecA Gene Acquisition: MRSA resistance is conferred through the acquisition of the mecA gene, which is carried on a distinct mobile genetic element called SCCmec (Staphylococcal Cassette Chromosome mec) 1
PBP2a Production: The mecA gene encodes for PBP2a, an alternative penicillin-binding protein that has low affinity for β-lactam antibiotics 2
Regulatory Control: Expression of mecA is controlled through a proteolytic signal transduction pathway comprising:
- MecR1: A sensor protein
- MecI: A repressor protein 1
Alternative Resistance Mechanisms
While the mecA gene is the predominant mechanism, other resistance pathways exist:
Mutations in Endogenous PBPs: Some MRSA isolates lack mecA but still show phenotypic resistance due to amino acid substitutions in the endogenous penicillin-binding proteins (PBPs 1,2, and 3) 3
RNA Polymerase Mutations: High-level β-lactam resistance (oxacillin MIC ≥256 μg/ml) can develop through mutations in either rpoB (RNA polymerase subunit β) or rpoC (RNA polymerase subunit β') 4
Type VII Secretion System: Components of the S. aureus Type VII secretion system have been implicated in high-level resistance development 4
Resistance Expression and Clinical Implications
Heterogeneous Expression: MRSA can display heterogeneous resistance, where only a small portion of the bacterial population expresses resistance, making detection challenging 5
Penicillinase Production: Beyond mecA, MRSA often produces β-lactamases (penicillinases), providing an additional layer of resistance 6
Community vs. Healthcare-Associated MRSA:
- Community-acquired MRSA (CA-MRSA) is generally susceptible to multiple antibiotics
- Healthcare-associated MRSA (HA-MRSA) tends to be multi-drug resistant 2
Ecological and Epidemiological Impact
Selection Pressure: Antibiotic use, particularly fluoroquinolones, can select for MRSA emergence 7
Transmission: MRSA can spread through direct contact, shared equipment, and environmental surfaces 2
Colonization: Certain populations have higher colonization rates, including children under 2 years, athletes, injection drug users, and individuals with recent antibiotic use 2
Clinical Relevance
Treatment Challenges: The resistance mechanism necessitates the use of alternative antibiotics like vancomycin, linezolid, daptomycin, or trimethoprim-sulfamethoxazole for MRSA infections 7
Emerging Resistance: Some MRSA strains are developing resistance to newer antibiotics through mutations in the mecA gene or other mechanisms 5
Diagnostic Implications: Detection of mecA or PBP2a is considered the gold standard for MRSA diagnosis, though phenotypically resistant strains lacking mecA may be misdiagnosed using molecular methods alone 3
Understanding the mechanisms of MRSA resistance is crucial for developing effective treatment strategies and preventing the spread of these resistant organisms in both healthcare and community settings.