## 1 Introduction  
### S. aureus and Resistance Mechanisms  
_Staphylococcus aureus_ is a substantial etiological agent of implant-associated infections [1; 2; 3; 4; 5], skin or wound infections [6; 7; 8; 9; 10], nosocomial infections [11], sepsis, and death [12]. _S. aureus_ is a dire pathogen because of its potential to acquire resistance to antibiotics [10; 13; 14; 15]. For example, the acquisition of the _mecA_ gene and production of a specific penicillin-binding protein (PBP2a) fortify _S. aureus_, resisting penicillin-resistant \(\beta\)-lactams (methicillin or oxacillin) [16; 17; 18; 19]. Apocalyptic outbreaks of methicillin-resistant _S. aureus_ (MRSA) have mainly been confined within hospital settings (hospital-acquired, HA-MRSA) and to immunocompromised patients. Then, MRSA outbreaks emerged from hospitals to community reservoirs. Healthy people could contract community-acquired MRSA (CA-MRSA) [6; 13; 14; 20; 21], especially those of low socioeconomic status (lack of medical care, crowding, poverty, and intravenous drug addiction) [22; 23; 24], and then die [21]. CA-MRSA was reported to cause community-acquired pneumonia associated with influenza (during the 2003-2004 influenza season) in the USA, eliciting severe illness and death [25]. CA-MRSA strains are distinct from HA-MRSA in possessing a characteristic Staphylococcus cassette chromosome _mec_ (SCC_mec_) type IVa and some carrying Panton-Valentine leukocidin (PVL) locus, producing PVL toxins [26; 27]. PVL toxin is associated with skin and soft-tissue infections, requiring increased surgical treatment, and rarely (i.e., in the USA), it is associated with invasive pneumonia and poor prognosis [27; 28]. The MRSA health problem is augmented via the simple five factors or simple five Cs, as termed via the Centers for Disease Control and Prevention (CDC) [29], facilitating MRSA transmission: (i) Crowding, (ii) skin-to-skin Contact (with colonized or infected person), (iii) Compromised integrity of skin, (iv) Contaminated fomites, and (v) Cleanliness deficiency. These factors are common, with increased risk of CA-MRSA infections among military personnel and day-care children [14; 24]. The reported resistance of MRSA to vancomycin worsens the bacterial antibiotic resistance scenario [30; 31; 32; 33; 34; 35]. This worse situation is because vancomycin is the bedrock of last-resort antibiotics treating notorious MRSA infections [36; 37; 38], besides linezolid and daptomycin [31]. If bacterial antibiotic resistance is currently a global bottleneck challenge, then the critical question here is: What are the future consequences of such bacterial antibiotic resistance? A direct answer is to return to the point of the pre-penicillin era, lack of new antibiotic classes, and the disengagement of pharmaceutical companies from the antibiotic research pipeline owing to the high economic burden of developing novel antibiotics and executing clinical trials [39; 40; 41]. In terms of numbers, by 2050, 10 million people would be expected to die every year globally [42; 43], and more than 1.2 trillion USD would be added to world health care costs every year [44; 45]. A cumulative global cost of up to 100 trillion USD would be expected if bacterial antibiotic resistance was not tackled [43]. What are the mechanisms behind the ruthless antibiotic resistance of bacteria? Evidence suggests that the essential mechanisms facilitating intrinsic (i.e., inherent or innate) bacterial antibiotic resistance are (i) alterations of bacterial membrane permeability and deoxyribonucleic acid (DNA), (ii) multidrug efflux pumps, and (iii) the inactivation of enzymes [46; 47; 48]. On the other hand, acquired bacterial antibiotic resistance is facilitated via chromosomal mutations or the acquisition of antibiotic resistance genes (horizontal gene transfer between bacteria) mediated by mobile genetic elements such as plasmids and transposons [4; 49; 50].