**3. Genetic aspect of resistance in** *S. aureus*

The genetic determinants of resistance to many antimicrobial agents are believed to have evolved prior to the era of antibiotic chemotherapy. Processes such as phosphorylation, glycosylation, acetylation whose inactivation or chemical transformation is the major cause of the MDR. The schematic diagram shows the possible ways of causing antimicrobial resistance (**Figure 3**) [1, 4, 10–12].

Methicillin-Resistant *Staphylococcus aureus* (MRSA) came into the focus of attention when the Methicillin-Susceptible *Staphylococcus aureus* (MSSA) started adopting a specific gene (methicillin-resistant gene) named as *mecA* which is intervened by a genetic element called Staphylococcus cassette chromosome (SCC) and is transferred into the MSSA via either conjugation or transformation (Horizontal gene transfer). As SCC elements are carrying the gene *mecA* so, the complex is named *SCCmec.* The complex consists of the mecA and several other regulatory genes such as *mecR1*, *mecI*. (**Figure 4**), Demonstrate a schematic diagram of the SSC*mec* element. There is also the presence of a specific complex named Cassette Chromosome Recombinase (CCR) that helps in the integration and excision of the element from the chromosome of *Staphylococcal* species [13–16]. The region, origin of replication (oriC) in the *S. aureus* chromosomal element is accompanied by a special gene named as orfX towards the downstream of the oriC. The gene orfX is popular for encoding a specific enzyme called ribosomal RNA methyltransferase and this gene also has direct repeat sequences that help to protect the Staphylococcus cassette chromosome (SCC). In this way, multiple SCC elements are placed one after another in tandem which results in the formation of the cluster of foreign genes and forms a chromosomal region whose name is oriC environ [13, 17, 18]. Now, there are mainly two types of MRSA. One, the Community-Associated MRSA (CA-MRSA), and the other one is Hospital-Acquired MRSA (HA-MRSA). CA-MRSA has been found to get transmitted among the population from crowded places and the CA-MRSA isolates are highly resistant against methicillin and penicillin as well. Minor skin problems, redness, itchiness, and pain are the symptoms of the body affected by CA-MRSA. HA-MRSA is acquired from the hospital or any health care center. oriC environ has many transposons and insertion sequences (IS) which are capable to induce deletion, recombination, chromosomal

#### **Figure 3.**

*Schematic diagram of antimicrobial resistance.*

#### **Figure 4.**

*A schematic diagram of SCCmec element. The SCC*mec *consists of two components mec. A gene complex and*  ccr *gene complex.* mec *gene complex helps to encode the methicillin resistance gene(*mec *A) and other two regulatory genes (*mecR1*,* mec1*).* ccr *gene complex takes care of the movement of the whole SCC element.*

inversion across oriC and this helps the *S. aureus* to maintain their survival strategy according to the environmental condition [18]. Horizontal gene transfer mediated by phage is one of the prime reason for the evolution of the *S. aureus*. It has been observed in the past studies that the Bacteriophages such as Staphylococcus Phage 80α is a specific helper bacteriophage that is required for the mobilization of SaPIs. This helps to carry the *Staphylococcus aureus* pathogenicity islands (SaPIs). SaPIs are known as mobile genetic elements which are the common residents in the genome of *S. aureus* and are transferred to other cells. These SaPIs are responsible for carrying several toxin genes and also superantigens [19, 20].

Plasmids are capable of carrying the resistant genes and also several toxic genes. In a recent study, it has been observed that when an *S. aureus* plasmid was sequenced which originated from a different bacterial environment, few trailblazing resistance genes named ampA and vgaC were discovered. The amp resistance gene is resistant to the antimicrobial drug named apramycin and the vgaC resistance gene is resistant against Streptogramin A, respectively. Along with these, many toxin genes are being carried on *S. aureus* plasmids such as exotoxin B (ETB) and enterotoxins (entA, entP, entG, entJ). R plasmids play a major role in mediating resistance among bacteria. Drug resistance genes are located in the R plasmids and they are also responsible in conferring multi drug resistance and induce less utilization of multiple antimicrobial therapy [21–23].

There is also support for the notion that some resistance determinants in staphylococci are derived from genes present in antibiotic-producing organisms. The *S. aureus* ermC methylase encoded on pE194 shares amino acid sequence

homology with the analogous methylase encoded by erythromycin-producing organisms such as *Streptomyces erythraeus* (ermE) [24].
