**5. Methicillin resistance in** *S. aureus*

Methicillin was introduced in clinical practice for the effective treatment of penicillin-resistant *S. aureus* infections [30]. After 2 years, the second wave of resistance against methicillin came into the light and the first report on methicillin resistance *S. aureus* (MRSA) strain was published by MP Jevons in 1961 [31]. Statistically, incidences of methicillin-sensitive *S. aureus* (MSSA), methicillinresistant *S. aureus* (MRSA), and vancomycin-resistant *S. aureus* (VRSA) infections have increased up to 54% in both hospital-acquired (HA) and community-acquired (CA) [32]. These antimicrobial-resistant infections cause a significant economic burden on public health. The economic burden of antibiotic resistance in Europe was estimated at almost 1.5 billion euros. However, USA spent more than 55 billion dollars each year on the treatment of antibiotic-resistant infections [9]. It was found that acquisition of methicillin resistance in *S. aureus* was primarily contributed by the integration of a *mecA* gene encoded for low-affinity penicillin-binding protein 2a or 2′ (PBP2a or PBP2′) into the staphylococcal chromosomal cassette (SCC*mec*) element of methicillin-sensitive *S. aureus* (MRSA) [33]. The expression of *mecA* in MRSA is induced by the interaction of methicillin and other antibiotics to the regulatory network. MecIR a regulatory protein, homologous to the BlaIR proteins, controls the expression of *mecA.* It is under the control of MecIR regulatory proteins that are homologous to the BlaIR proteins that regulate BlaZ expression [34, 35]. The SSC*mec* is located specifically with an unknown gene (orfX) of the staphylococcal chromosomal. The function of the unknown gene is mediated by two recombinases termed as *ccrA* and *ccrB* that help in the site-specific integration or excision of DNA elements from the staphylococcal chromosomal [36, 37]. The insertion sequence, transposon (Tn554) or erythromycin- and spectinomycin-encoded resistance genes, and tobramycin and kanamycin resistance-encoded pUB110 plasmid can be additionally jumped in the SSC*mec* region. Typing of SSC*mec* elements is fundamental for the molecular epidemiology of MRSA and categorized majorly into five types, that is, type I-V [38]. The SSC*mec*-type I-III elements are present in hospital-acquired MRSA strains, which are typically resistant to non-β-lactam antibiotics. In contrast, SSC*mec*-type IV-V are only resistance to methicillin, which are primarily present in community-acquired MRSA (CA-MRSA). Different studies revealed that multiple insertions of SCC*mec* elements in the staphylococcal chromosome of MSSA strains yield a MRSA lineage. The *mecC* gene, homolog to *mecA* gene, exhibits 68.7% nucleotide identity is identified in *S. aureus*, *Staphylococcus sciuri,* and *Staphylococcus xylosus* strains [39]. The recent studies revealed that *mecC* carrying *S. aureus* contributes in methicillin resistance in the human population by up to 2.8% of MRSA strains [40–42], while no report was found on mecB-carrying *S. aureus* resistance to methicillin. In many MRSA strains, the expression of *mecA* is also affected either by the synthesis of truncated MecIR regulatory proteins or by repression by *β*-lactamase regulators BlaI and BlaR. The Mec and Bla regulatory proteins can alter the functional behavior and expression of PBP2a-encoded gene in MRSA strains. In a short period, MRSA strains have been identified all around the globe particularly Asia, USA, and Europe [43]. In spite of the rapidly spreading of methicillin resistance, MRSA exhibited broad-spectrum drug resistance against methicillin, penicillins, cephalosporins, and carbapenems. The MRSA cases were increased in hospitals and other healthcare facilities (hospital-acquired), and in communities (community-acquired infections). People with immediate surgeries or stay in healthcare facilities are at MRSA higher risk. Infection also spreads if a medical device has been put in their body or when they come close to contact with MRSA-infected patient. MRSA spreads in communities through uncovered or draining wounds mostly associated with crowded living, sharing personal items,

recent stays in healthcare facilities, etc. In 2017, CDC reported that more than a 0.3 million cases and over 10,000 deaths from MRSA-related infections are estimated in-hospital patients with more than 1.7 billion healthcare burdens in the United States. This figure represents mere a 50% of all the mortalities caused by antibioticresistant bacteria. The prevalence of MRSA infections in India has been reported to increase from 29% in 2009 to 47% in 2014 [35].
