Mechanism of β-lactam resistance of Staphylococcus aureus , Mechanism of methicillin resistance of Staphylococcus aureus

Mechanism of β-lactam resistance of Staphylococcus aureus

β-lactamase enzymes cause resistance of cell to β-lactam antibiotics by inactivating β-lactam antibiotics. β-lactamase inactivates β-lactam antibiotics by disrupting amide bond of βlactam ring [5]. Expression of the blaZ gene that is located in plasmid or transposon and encodes β-lactamase is regulated by blaI and blaRI that are own regulators. In the lack of β-lactam antibiotic, BlaI that bound to promoter-operator region repress blaZ gene, blaI-blaRI operon, so transcription of blaZ is not happen. In the usage in treatment or supplementation of β-lactam antibiotic to growth media, β-lactam binds to BlaRI that is a β-lactam-sensing signal transducer, and then, intracellular zinc metalloprotease domain of BlaRI is separated and cleaves BlaI that is already bound to operator. By this way, in the presence of β-lactam, blaZ is transcribed to β-lactamase that permits MRSA to grow by inactivating β-lactam.



(a).

Induction of staphylococcal β-lactamase synthesis in the presence of the β-lactam antibiotic penicillin. I. The DNA-binding protein BlaI binds to the operator region, thus repressing RNA transcription from both blaZ and blaR1-blaI. In the absence of penicillin, β-lactamase is expressed at low levels. II. Binding of penicillin to the transmembrane sensor-transducer BlaR1 stimulates BlaR1 autocatalytic activation. III–IV. Active BlaR1 either directly or indirectly (via a second protein, BlaR2) cleaves BlaI into inactive fragments, allowing transcription of both blaZ and blaR1-blaI to commence. V–VII. β-Lactamase, the extracellular enzyme encoded by blaZ (V), hydrolyzes the β-lactam ring of penicillin (VI), thereby rendering it inactive (VII). 


Mechanism of methicillin resistance of Staphylococcus aureus

(b).

Resistance to methicillin, oxacillin, and nafcillin that are semisynthetic β-lactamase-insensitive β-lactams has developed by acquiring of the mecA gene [5]. MRSA is not only resistant to methicillin, but also resistant to all β-lactams.

Mechanism of S. aureus resistance to methicillin. Synthesis of PBP2a proceeds in a fashion similar to that described for β-lactamase. Exposure of MecR1 to a β-lactam antibiotic induces MecR1 synthesis. MecR1 inactivates MecI, allowing synthesis of PBP2a. MecI and BlaI have coregulatory effects on the expression of PBP2a and β-lactamase.

mecA gene expression is regulated by mecI and mecRI that are own regulators. In the lack of β-lactam antibiotic, MecI that bound to promoter-operator region repress mecA, and mecImecRI operon, so transcription of mecA is not happen. In the usage or supplementation of βlactam antibiotic to growth media, β-lactam binds to MecRI that is a β-lactam-sensing signal transducer, and then, metallo-protease domain of MecRI that is placed in cytoplasmic site is separated and cleaves MecI that is already bound to operator. By this way, mecA is transcribed to PBP2a of which affinity is low to β-lactams [49]. Low affinity of PBP2a to β-lactams permits MRSA to grow as a result of peptidoglycan synthesis in the presence of β-lactams concentrations that can inactivate transpeptidase activity of PBPs. PBP2a that belongs to PBPs contains transpeptidase domain and non-penicillin-binding protein.








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