The SCCmec genomic island confer resistance to Beta-Lactams , the island has been shown to encode resistance determinants to other antibiotics.

Hi Sanmugapriya, as you said- the important mechanism of resistance employed by the MRSA strains of S. aureus is altering PBP.

MRSA gains resistance to the β-lactam antibiotics by means of enzymatic inhibition as well as altering target. The gene conferring resistance to the β-lactam antibiotics is located on the mecA gene and is easily transferred among bacteria by means of a plasmid vector. Since β-lactams bind PBPs on the cell membrane of S. aureus, the main strategy of resistance is to alter these proteins. Once the organism alters the PBPs, the β-lactam antibiotics have a significantly decreases affinity for the substrate (PBPs). This is the main mechanism of resistance employed by the MRSA strains of S. aureus . 

VRSA:

Vancomycin-resistance has been traced to the presence of the vanA gene, which operates by the same mechanism to prevent vancomycin from binding their substrate on the peptidoglycan of S. aureus.

Thanks for your answer Dr.Godfred. I  would like to know other mechanisms like efflux pumps, virulence factors, etc. So it is only PBP2a expression which is the main mechanism or else other mechanisms also involved? If yes, what is their level of existence? 

How about the expression of beta-lactamases? And also, in vancomycin-resistant-MRSA, the thickened cell wall represents altered peptidoglycan biosynthesis, which simply means that the vancomycin will be trapped in the cell wall because of decreased cross-linking of peptidoglycan stands.

Staphylococcus aureus is the precursor of Methicillin resistant Staphylococcus aureus (MRSA).  This microorganism can exemplify better than any other human pathogen the adaptive evolution and plasticity of bacteria in the antibiotic era.  Primarily isolated in nosocomial setting, MRSA strains have now spread into the community, thus further complicating the management of serious infections caused by this potentially life threatening superbug.  

Infections caused by MRSA include, skin, soft tissue, bone and  joint infection, medical device related infection, pneumonia, blood stream infections, infective endocarditis, aortic root abscess, discitis, spinal epidural abscess, toxic shock syndrome, toxic epidermal necrolysis, necrotising fasciitis and abscess formation virtually in every organ of the body.  MRSA has demonstrated a unique ability to quickly respond to each new class of antibiotics with the development of a resistance mechanism, starting with penicillin and methicillin, to vancomycin and teicoplanin, and until the most recent to linezolid and daptomycin.

I shall comment below on various mechanisms of resistances that MRSA can develop

1.  Resistance in MRSA is primarily mediated by the mecA gene. The mecA gene encodes for a novel penicillin-binding protein, PBP-2a.  In MRSA, exposure to anti-staphylococcal antibiotics e.g. methicillin, flucloxacillin, dicloxacillin, nafcillin, can inactivate the 4 high-binding-affinity PBPs normally present.  However, PBP-2a, which displays a low affinity for methicillin, takes over the functions of these PBPs, permitting the bacterial cell to grow in the presence of antibiotics. Regulation of the methicillin-resistant phenotype and production of PBP-2a are influenced by the action of other genes. Two genes mecR1 and mecI located upstream from mecA control the expression of PBP-2a.

2.  Enzymatic inactivation of antibiotics by penicillinase production.  This will make it resistant to penicillins other than anti-staphylococcal agents e.g. amoxicillin, ampicillin, benzyl penicillin, and penicillin V.

3.  Aminoglycoside-modifying enzymes will make MRSA resistant to gentamicin, tobramycin, netilmicin, and amikacin.

4.  Alteration of the target with decreased affinity for the antibiotic e.g. production of D-Ala-D-Lac of peptidoglycan precursors instead of D-Ala-D-Ala will confer resistance to vancomycin and teicoplanin.

5.  Trapping of the antibiotic will make it resistant to vancomycin and possibly to daptomycin.

6.  Efflux pumps mechanism will produce resistance to fluoroquinolones and tetracyclines.

7.  Complex genetic arrays e.g. staphylococcal chromosomal cassette mec elements or the vanA operon, have been acquired by S. aureus through horizontal gene transfer. 

8.  Resistance to other antibiotics, including fluoroquinolones, linezolid and daptomycin, have developed through spontaneous mutations and positive selection.

Detection of the resistance mechanisms by molecular genetic studies is an important support function to antibiotic susceptibility surveillance studies in MRSA and S. aureus.

To date, vancomycin remains the drug of choice for the treatment of infections caused by MRSA, although it is intrinsically less active than the anti-staphylococcal penicillins. In addition, high MIC strains of MRSA have recently emerged to vancomycin, which are associated with high rates of failure of vancomycin therapy in MRSA pneumonia and bacteraemia, resulting in higher burden of morbidity and mortality. 

As a result alternative agents active against MRSA have been developed and marketed which include linezolid, daptomycin, and ceftaroline.  If there is a poor response to vancomycin or teicoplanin, an alternative agent should be considered for therapy of serious MRSA infections e.g. bacteraemia, endocarditis, spinal discitis, perinephric abscess, or MRSA pneumonia.

Sayed S Bukhari MD FRCPath

Consultant in Infection

EAST Midlands, UK

Very thanks to Dr.Sayed Bukhari for listing out various resistance mechanism. 

You are very welcome!

SSB

Dr.Bukhari's eloborate note on the mechanism of resistance by MRSA is worth reading.

Resistance in MRSA is primarily mediated by the mecA gene. The mecA gene encodes for a novel penicillin-binding protein, PBP-2a. In MRSA, exposure to anti-staphylococcal antibiotics e.g. methicillin, flucloxacillin, dicloxacillin, nafcillin, can inactivate the 4 high-binding-affinity PBPs normally present.

Resistance in MRSA is primarily mediated by the mecA gene. The mecA gene, which is located in the staphylococcal chromosomes, enhances virulence of Staphylococcus by causing resistant to methicillin antibiotics. The mecA gene encodes for nonnative gene encoding a penicillin-binding protein (PBP2a), with significantly lower affinity for β-lactams. PBP-2a, which displays a low affinity for methicillin, takes over the functions of these PBPs, permitting the bacterial cell to grow in the presence of antibiotics.