**3.7 Resistance to new class of antibiotics: pleuromutilins**

In 1951 a compound Pleuromutilin a class of antibacterial which is isolated from a fungus called Pleurotomariids. Pleuromutilin and its natural molecule found to be effective against Gram-positive bacteria. For veterinary use Tiamulin used in livestock for the treatment of gastrointestinal and respiratory disease. Valnemulin is a second veterinary systemic Pleuromutilin antimicrobial approves and widely use in Asia and Europe. For systemic human use lefamulin was synthesized in 2006, lefamulin is novel pleuromutilin drug effective against most MRSA strains [100]. In phase 2 lefamulin was non inferior to intravenous Vancomycin. Pleuromutilin interferes with the process of protein synthesis by inhibiting the 50s subunit of the ribosome binding at site called peptidyl transfer centre [101, 102]. They specifically target the inhibition of initiation of translation. The extensive use of tiamulin and valenemulin for decades in livestock leads to MRSA strains and their mechanism of resistance to pleuromutilin are well studied. One of the resistance mechanisms involves alteration of target site on the ribosome which may require three or more mutations to develop resistant phenotype [103–105]. Resistant clones may be formed when *Staphylococcus aureus* acquire new genes by horizontal gene transfer including transferable cfr gene methylation a specific site on 23S rRNA. This methylation by cfr gene product results in resistance to several class of antibiotics including pleuromutilin, linezolid, streptogramin, phenicol, and lincosamides. In *S. aureus* is the family of at least four vga genes with variants, including vga(A)v, vga(A), vga(C), and vga(E), as well as lsa(E), all result in ribosomal protection results in cause of pleuromutilin resistance in S. aureus. Plasmid or transposons can carry strains vga(A) may become transmissible among strains. In ST398 livestock-associated MRSA strains found vga(c) strain also be carried on plasmid. The spread of mobile genetic elements among animal and human S. aureus strains raises concern for the emergence of widespread pleuromutilin resistance among human strains if drugs in this class are widely used [106, 107].

### **3.8 Resistance to mupirocin**

Mupirocin was used as a decolonizing agent. It is widely used in CA-MRSA epidemic United States in 1990. But it was discovered in in 1970. Resistance to mupirocin by MRSA developed [10, 108]. Mupirocin resistance is developed due to ileS-2 gene [109]. The mupA and mupB genes responsible for resistance to mupirocin these genes encode novel isoleucyl-tRNA synthetases and can be carried out by *Mechanistic Insights of Drug Resistance in* Staphylococcus aureus *with Special Reference... DOI: http://dx.doi.org/10.5772/intechopen.100045*

plasmids [110]. The threes aspect of REDUCE-MRSA study was cluster-randomized trial that evaluate screening, isolation, and decolonization with chlorhexidine and mupirocin in intensive care unit patients [111]. Mupirocin is best suitable option for MRSA nasal decolonization but shows some side effects. Development of novel decolonization agent should be our propriety. We can also develop agents that can act synergistically with mupirocin as recently described [112, 113].

#### **3.9 Resistance to lipoglycopeptides**

Dalbavancin, oritavancin, and telavancin, the semisynthetic derivatives of glycopeptides are the three lipoglycopeptides available in the US. Glycopeptides usually inhibits bacterial cell wall synthesis by binding to D-alanyl-D-alanine (D-Ala-D-Ala) terminal of growing peptidoglycan chains [114]. Due to their distinctiveness in structural modifications of each drugs heptapeptide core, lipoglycopeptides are more powerful than vancomycin which contains lipid side chain that helps in holding the drug to cell membrane providing stability and an increase in concentration of local drug. In case of oritavancin and telavancin their interaction with the cell wall promotes another mechanism of action as concentration-dependent depolarization of cell membrane leading to increase in permeability. Because of the structure of oritavancin it allows several other mechanisms of action which includes binding to the secondary site in peptidoglycan chains, pentaglycyl bridging segment of lipid II, transpeptidation inhibition and RNA synthesis inhibition [115, 116]. A survey study conducted from 2010 to 2014 in US and Europe showed 99.9% isolates of S. aureus susceptible to oritavancin and 98% isolates susceptible to dalbavancin in global survey during 2002 to 2012 [117] with rare Lipoglycopeptide resistance among S. aureus. Recently for dalbavancin, Resistance in some clinical isolates has been reported. On structural analysis showed an increase in the thickening of cell wall and abnormal cell wall construction in dalbavancin non-susceptible isolates [118, 119].

### **4. Evolution of** *Staphylococcus aureus* **as superbug**

Alexander Flaming accidently discovered penicillin as fungal contaminant also having bactericidal effect against Staphylococcus aureus which in turn led to bulk production of this antibiotic [120]. Consequently, death rate due to bacterial pneumonia and meningitis fell down during World War II. Penicillin was discovered to act by breaking peptidoglycan assembly within bacterial cell wall followed by cell death due to osmotic fragility [121]. In early 1940's death rate of Staphylococcal infections was approximately 80%. However, resistance *Staphylococcus aureus* strains were observed after overuse of penicillin which got predominant in 1945 [122–124]. The major cause of this resistance was the eventual formation of plasmid encoded-lactamase which found to have ability of hydrolysing active moiety i.e. lactam ring of penicillin [124, 125]. The ability of plasmid encoded-lactamase to readily transfer which rises the penicillin against bacterial resistance rate up to 90-95%. Moreover, in 1950 a resistant clone of *Staphylococcus aureus* called phage 80/81 was responsible for the outbreak pandemic of skin infections, sepsis of skin and pneumonia. Initially it was concerned inside the premises of hospital but eventually it outspread within the public outside [126]. Australia, America and Canada were the majorly effected countries during this epidemic which lasted for almost 10 years until a methicillin came into market [127]. It was purposely designed in 1959 for the lactamase resistance strains of staphylococci and their treatment but surprisingly it worked efficiently for only one year because later on the methicillin resistance strain of Staphylococcus aureus was first observed in 1961 in United

Kingdom [128]. The major cause of acquired resistance was mecA gene at specific site of chromosome. mecA gene was reported to encode an alternative penicillin binding protein gene called PBR2a and PBR2 which possessed very little binding affinity against penicillin, methicillin, nafcillin and cephem derivatives [129]. However, this resistance was found to be different from penicillin acquired resistance as it included broad spectrum antibiotics i.e. almost entire class of lactams except ceftaroline and ceftobiprole [130]. Adding on, a genetic element was found to be the prime carrier of mecA gene and was responsible for the broad-spectrum resistance as well as outbreak of its infections in 1980 [131]. Few countries that had major impact were Ireland, United States and United Kingdom. Despite the fact that it was first observed in 1961 it was highly appeared in 1980 and responsible for pandemic. MRSA was major risk for people having low immunity therefore death rate was approximately 15 times and bacteraemia was observed to be 24-fold than earlier [132]. MRSA outspread in Europe in early 1970's was confirmed to be caused by one of the MRSA clones called 83 phages; an archaic clone which eventually became demolished and replaced by another five lineage clones of MRSA by 1980's. The foremost MRSA infection case was observed in Sydney in 1965 followed by sporadic nosocomial MRSA infections in Melbourne, Sydney and other cities of Australia [133, 134]. Western Australia was rather reported to be free from these infections until late 1980's when gentamicin susceptible Non-Multidrug Resistant (MDR) MRSA was observed first which later on outspread very fast [135, 136]. However, the quickest outbreak of MRSA was observed in Boston, United States of America in 1968 [137]. Number of cases increased drastically from 2.4–29% from 1968 to 1975 which rose to 56.1% till 2003 [138, 139]. Moreover, high rate of MRSA infections was observed in other parts across the world also [140–147]. In japan MRSA infections invaded in academic hospitals in 1980 which later become community spread in 1990 [148]. Number of MRSA infected patients were comparatively lower than observed in America however mild increase was observed in frequency of MRSA patients from 3.8% - 9.6% in 1990-1994. But when only the outpatients were considered the MRSA infection rate was observed to be drastically rose from 4.5-35% in 1994 [149, 150]. The first clinical isolate of MRSA known to carry PVL gene in CA-MRSA era was observed in 2003. Furthermore, according to the data given by National Infectious disease register in 10-fold increase in MRSA infectious cases i.e. 120-1458 has been found in 2004. Meanwhile the countries like Norway, Sweden, Denmark and Netherland were found to be free from these infections due to strict surveillance. In the period of six years (2000-2006), Eastern Australia and Queensland were reported to have an increase of 75-315 patients per million. MRSA strains prevalent in these countries were majorly non-MDR strains which have susceptibility to ciprofloxacin and resistant at least to one of the β-lactams. It was a period of high emergence of non-MDR strains of MRSA. In 2011, surveillance studies were carried out in Asian countries to find out the patients with MRSA infections [151–154]. Data revealed HA-MRSA prevalence was highest in Sri Lanka (86.5%) followed by Vietnam (74.1%), South Korea (65%), Thailand (57%) and Hong Kong (56.8%). However, the rate of infections in Indians and Philippines was quite low i.e. 22.6 and 38.1% approximately. Infected patients and staff were the major reason for the outbreak of MRSA across the countries and continents. With time and resistance MRSA had been found to be emerged, declined and modified accordingly. When initially observed, the MRSA strains were confined only to the hospitals and health care centres which later on becomes a pandemic via community spread. Moreover, livestock was also found to be affected by MRSA infections. According to last research report vancomycin was an antibiotic susceptible to MRSA however later on some investigations demonstrated Vancomycin Intermediate resistance *Staphylococcus aureus* (VISA) and Vancomycin Resistant *Staphylococcus* 

*Mechanistic Insights of Drug Resistance in* Staphylococcus aureus *with Special Reference... DOI: http://dx.doi.org/10.5772/intechopen.100045*

*aureus* (VRSA) in some clinical strains. If this trend gets continued to be followed further then MRSA will undoubtedly become completely resistant strain which is a serious topic of concern in field of infectious diseases [155–158].
