**4. Resistance against antibiotics**

Due to the high resistance against methicillin and after the failure of the drug, Vancomycin was playing a major role in treating most MRSA infections. Isolates of *S. aureus* were taken from a surgical wound of a Japanese baby and it was observed that the infection was not responding to the drug called Vancomycin. Vancomycin, is an antibiotic made up of glycopeptide and was initially used for the treatment of the MRSA strains as the efficacy of this drug was quite prominent but eventually because of prolong usage of the drug, it was resistant to MRSA infections. The resistance was not via the acquisition of vanA by MRSA infection-causing strain but this was because of unusual thickening of the cell wall which is rich in dipeptides and this results in the decreasing of the drug availability in the body. Despite the issues, in the year 2000, Vancomycin was considered to be one of the prominent drugs against the MRSA strains. The mechanism of the resistance is predicted to be a plasmid-mediated transfer among the species. The genes vraS, msrR, rpoB and graR were found to be mutated which was responsible for the resistance against the Vancomycin [13, 25–27]. Other than Methicillin and Vancomycin, Penicillin and Quinolones were also given to *S. aureus*.

In case of Penicillin, R plasmids encode the enzyme called as *penicillinase,* the plasmid gene that carries the enzyme is *blaz*, and the organisms that were resistant to penicillin were having this gene which inactivated the antibiotic by splitting the β-lactam ring. Slowly, this became a threat and major resistance towards penicillin antibiotic emerged world wide [28–30]. Use of Methicillin started when Penicillin failed to cure the Staphylococcal infections. After major failure of both these antibiotics, Quinolones were used. Quinolones destroy the bacteria by attacking and inhibiting their bacterial topoisomerases which generally ease the super coiling of DNA and also separates DNA strands. Moxifloxacin and Gemifloxacins are useful against the Gram-Positive bacteria but unfortunately *S. aureus* again developed resistance against quinolones [31, 32]. *S. aureus* developed resistance against fluoroquinolones by overexpression of the NorA efflux pumps. Similarly, point mutation is another way by which this organism becomes resistant to quinolones. Point mutation in the subunits of topoisomerase takes place. Such as, point mutation at Gr1A in topoisomerase IV subunit and in GyrA, subunit of Gyrase [28].

#### **4.1 Transmission pattern of resistance**

Transmission of MRSA infections can take place from person to person who is contaminated with such infections. Proper hygienic condition is required to maintain infection from getting spread. Although the mode of transmission of infections mainly relies upon direct contact but contact with contaminated fomites can also transmit the infection. Several other factors of the host such as immunocompromised patients, defects in neutrophils, or destruction of the skin barriers can also give rise to the infections. *Staphylococcus aureus* has shown evolutionary changes in it and this phenomenon completely relies on the plasmid gene transfer mechanisms. The conventional mechanisms such as horizontal gene transfer popularly conjugation and transformation are followed by the strains to spread the resistance among the population or community but there is a very unique mechanism of *Staphylococcus* named SaPI-helper phage [33, 34]. Through all the studies it is quite evident that plasmids are the fundamental element that is helping in mediating the virulence and the resistance genes among the population of the *S. aureus* [35–37].
