Staphylococcus (S.) aureus is a ubiquitous pathogenic bacterium. Methicillin-resistant S. aureus (MRSA) is among the leading causes of nosocomial pathogens which decipher the multidrug-resistance (MDR) phenotype ^[1][2][3][1,2,3]. MRSA employs various mechanisms to resist drugs, such as cell wall thickening, efflux of compounds, enzymatic destruction, and target variation ^[4][5][6][4,5,6].

MRSA infections encompass a wide range of manifestations and are a major life-threatening priority worldwide ^[7][8][7,8]. MRSA is resistant to β-lactam antibiotics. These strains carry a modified penicillin-binding protein (PBP) known as PBP-2a (encoded by either mecA or mecC gene) inherently exhibiting resistance to various β-lactams such as oxacillin, methicillin, and cefoxitin [9]. MRSA is classified based on genotypic diversity and according to various staphylococcal cassette chromosome mec (SCCmec) types including SCCmec (I-XIII) as substantial markers of MRSA epidemiology. The SCCmec gene cassette carries the mecA or mecC genes in addition to other genes associated with aminoglycosides, macrolides, and fluoroquinolones resistance [10]. MRSA is classified into three main categories including healthcare (HA-MRSA), community (CA-MRSA), and livestock-associated (LA-MRSA) strains each with special virulence and resistance patterns ^[7][10][7,10]. HA-MRSA is responsible for nosocomial infections globally and usually carries SCCmec types I, II, or III. CA-MRSA has been recorded in patients without or by negligible contact with healthcare settings. These strains usually carry SCCmec elements IV, V, and pvl genes. The latter is associated with the Panton–Valentine leukocidin. The LA-MRSA isolates are mainly associated with livestock origins and usually carry SCCmec IVa and SCCmec V elements. Life-threatening infections caused by LA-MRSA have been previously recorded, highlighting the possibility of zoonotic risk ^[11][12][11,12]. In humans, MRSA can cause severe pyogenic infections of the skin and soft tissue, endocarditis, septic arthritis, pneumonia, osteomyelitis, and otitis media ^[9][13][9,13].

Although the colonization of S. aureus on host surfaces is not harmful, overcoming the host’s innate immunity leads to invasive deep infections. MRSA causes various cutaneous and deep infections such as folliculitis, impetigo, cutaneous abscesses, pyomyositis, necrotizing pneumonia, and fasciitis [14]. HA-MRSA causes implant or surgical site and catheter-associated infections. Bacteremia-related infections include disseminated infections such as descending urinary tract infections, endocarditis, and osteomyelitis. Thereby, the eradication of the bacterium is a concern considering recurrent infections. The bacterium virulence regulation is exerted by a set of global regulatory circuits (two-component systems, TCS, accessory gene regulatory, Agr, and quorum-sensing, QS) which affect gene expression following environmental signals. Additionally, S. aureus responds to internal stimuli in the form of QS autoinduced signaling. AgrBDCA regulates RNA effector RNAIII ^[15][16][15,16].

Biofilm formation is an indispensable mechanism of resistance to antimicrobials and for the environment of host responses. The polysaccharide intercellular adhesin (PIA) mediates the bacterial binding to host cells. Some other major surface adhesin proteins include fibrinogen binding protein (FnBP) A and B, surface binding protein A (Spa), cell wall-anchored proteins (CWP), clumping factors (Clfs) A and B, and surface binding protein (SasG) ^{[17][18][19][20]}[17,18,19,20].

Following the bacterial attachment to the cells and colonization, pathogenesis is initiated and developed via the production of toxins, exoenzymes such as exfoliative toxins (ETs), Panton–Valentine leukocidin (PVL), toxic shock syndrome toxin1 (TSST1), phenol-soluble modulins, leukotoxin and haemolysin, lipases, proteases and nucleases, and immunomodulators or immune evasion gene clusters (IEC1 and IEC2) [21].

Phenol-soluble modulins, leukotoxin, and haemolysin are known as pore-forming toxins which lyse the host cells. α-, β-, γ-, and δ-hemolysins of S. aureus cause the lysis of erythrocytes, epithelial and endothelial cells, monocytes, damage of the epithelium, and induction of apoptosis. Leukotoxins or PVL target and destroy white blood cells such as macrophages, monocytes, and neutrophils. These include LukDE, LukAB, LukS-PV, and LukF-PV. PVL is associated with soft tissue and skin infections in both MSSA and MRSA ^[22][23][22,23].

Phenol-soluble modulins (PSMs) including PSMα1–PSMα4 play a substantial role in bacterial pathogenesis via cell lysis, inflammation, immune regulation, and biofilm formation or detachment [24]. Exfoliative toxins (ETA-ETD) cause staphylococcal scaled skin syndrome (SSSS) which is associated with dehydration, loss of superficial skin layers, and secondary infections which are not significantly different from MSSA and MRSA [25]. Staphylococcal enterotoxins (SEs) and TSST-1 act as superantigens which are T-cells mitogens. SEs cause food poisoning and gastrointestinal problems such as emesis. TSST1 causes the release of extraordinary amounts of pro-inflammatory cytokines [26]. In addition to humans, MRSA has long been recognized globally to colonize numerous wild and domesticated livestock animals and develop infections ^{[27][28][29][30][31]}[27,28,29,30,31]. The widespread distribution of MRSA among livestock is largely due to the indiscriminate prescription/consumption of antimicrobials for animal breeding or agricultural activities. For example, it has impacted more than 40% of pig farms, 20% of cattle farms, and 20% to 90% of turkey farms in Germany. Numerous studies have shown that there is a high risk of MRSA colonization and infection in humans who come into contact with livestock ^[32][33][32,33]. MRSA is repeatedly recorded in dairy farms as a cause of mastitis with failure in elimination due to its resistance against β-lactam antibiotics employed for related infections [34].

MRSA strains employ various virulence factors to invade the host and develop resistance [6]. The development of resistance to last-resort antimicrobial treatments such as glycopeptides (vancomycin and teicoplanin) is a crisis in the eradication of vancomycin-intermediate S. aureus (VISA) or vancomycin-resistant S. aureus (VRSA) ^[17][35][17,35]. For skin infections (impetigo) of MRSA, mupirocin and fusidic acid or alternative 1% hydrogen peroxide (H₂O₂) are recommended. For abscesses, in conditions of neutropenia, cell-mediated immunity deficiency, or severe infection, there is a need for co-trimoxazole or clindamycin treatment. For cellulitis and soft tissue infections, glycopeptides, tigecycline, and linezolid are useful. Susceptibility testing is strongly recommended prior to the utilization of antimicrobial drugs. Antimicrobial therapy necessity should be evaluated when infections are observed due to costs and risk of resistance evolution. The term “superbug” is defined as a strain developing vast antibiotic resistance [36].

Combination therapies have demonstrated substantial bactericidal effects against MRSA. The combination of carbapenems with linezolid, and each of imipenem/fosfomycin/gentamicin/oxacillin/rifampin and daptomycin have deciphered acceptable anti-MRSA effects ^[37][38][39][37,38,39]. A β-lactams and daptomycin combination facilitates its binding and mitigates resistance development ^[40][41][40,41]. Additionally, the combination of gentamicin/β-lactams/rifampin and vancomycin has outlined significant effects ^[42][43][42,43]. However, the combination of vancomycin and β-lactams has had nephrotoxicity according to clinical trials ^[44][45][46][44,45,46].

Natural combination therapies using Polysporin and Neosporin peptides have also exerted anti-MRSA effects [47]. Major chemotherapy approaches to combat MRSA have included telavancin, teicoplanin, ceftaroline, vancomycin, and oxazolidinones ^[48][49][48,49]. The combination of β-lactam and either arbekacin or vancomycin is recommended against MRSA. Notably, granulocyte counts are also recommended for antibiotics consumption ^[50][51][50,51]. Ceftaroline fosamil has exhibited substantial anti-MRSA effects ^[52][53][54][52,53,54]. Daptomycin and ceftaroline have exhibited higher bactericidal effects and linezolid has exerted strong effects on bacteremia.

As the first clinically applied anti-MRSA oxazolidinones, linezolid is a promising antibiotic with low resistance development to MRSA. However, epidemiological data have unraveled that linezolid resistance among MRSA isolates is in enhancement alongside novel antimicrobials quinupristin/dalfopristin (Q/D), daptomycin, and tigecycline ^[55][56][55,56]. Major drawbacks in the conventional approaches to MRSA eradication using antibiotics include non-specific effects which kill human beneficial bacteria, adverse/toxic effects, drug resistance development, and the high cost and time-consuming development of new drugs.

The efficient, non-toxic, proper, accurate, and cost-effective eradication of MRSA infections has been recently achieved through the application of nanocarriers or nanoparticles (NPs) ^[57][58][57,58]. NPs have a size range of 1 to 100 nm. The physicochemical properties of NPs and lower costs are gaining attention for use as antimicrobial agents ^{[59][60][61][62]}[59,60,61,62]. NPs have exhibited antimicrobial effects, particularly those synthesized using green methods [6]. NPs can also be used for the detection of MRSA [63]. The main mechanisms of NP antibacterial effects include an impairment in metabolism or bacterial integrity (CuNPs), replication and transcription disruption, tRNA, ATPases, membrane-bound enzymes and biofilm inhibition, protein denaturation (AgNPs), and reactive oxygen species (ROS) production ^[64][65][66][64,65,66]. Various NPs such as silver (Ag), gold (Au), and lower-cost NPs such as nickel (Ni), titanium-oxide, (TiO), zinc oxide (ZnO), silica (SiO2), and bismuth (Bi) NPs have deciphered efficient bactericidal effects against MRSA in vitro and in vivo ^{[67][68][69][70][71]}[67,68,69,70,71]. Various methods of NP delivery to cells for antibacterial activity include polymeric NPs, liposomes, carbon NPs, and metal or metal-oxide NPs. ZnO could eliminate MRSA skin infection at 1875 mg/mL possibly via amino acid synthesis inhibition [70]. TiO2 NPs produce free radicals which kill MRSA [72]. Cu-doped ZnO nanorods have exhibited more potential effects than that of ZnO singly [73]. Cefotax-based magnetic NPs have exhibited promising anti-MRSA effects against isolates originating from livestock and dairy sources [58]. Interestingly, S,N-GQDs/NiO nanocomposites have exerted extraordinary anti-S. aureus effects in vitro with minimum inhibitory (MIC) and bactericidal (MBC) concentrations values of 0.4 and 0.8 mg/mL, respectively [74]. Nickel oxide nanoparticles (NiO NPs) exhibit promising traits such as biocompatibility, thermal and chemical stability, and interesting optical characteristics. The development of NiO nanocomposites has improved their bactericidal effects. The simple synthesis of a CdO–NiO–ZnO nanocomposite using the microwave method also exhibited antibacterial effects against Gram-positive and Gram-negative species ^[75][76][75,76]. In addition, NiOCuO-10%RGO also demonstrated substantial antibacterial activity [74]. NPs can specifically carry drugs and enter into cells via endocytosis. A few NPs for the eradication of MRSA have been used for clinical trials. PLGA-rifampicin NPs have decreased the MIC against MRSA from 0.0008 to 0.002 µg/mL [77]. Vancomycin-loaded hydroxyapatite increased the vancomycin release and improved bone regeneration [78]. The combination of levofloxacin and AgNPs unraveled a synergistic effect with 0.5 and 10 µM against control strains and MRSA, respectively [79]. The application of liposome-albumin-vancomycin has decreased toxicity and improved the anti-MRSA activity [80].

It was revealed that Chitosan/Gold Nanoparticle/Graphene Oxide could separate, identify, and eradicate MRSA superbugs within water contaminants. Chitosan has a positive charge and can trap these strains. In a study by Gupta, engineered polymer NPs exerted anti-biofilm effects against MRSA strains at non-toxic levels ^[81][83].

Mesoporous silica nanoparticles (MSNs) carrying enzymes have exhibited anti-biofilm (dispersal) effects against S. aureus, decreasing the bacterial cells efficiently after 24 and 48 h ^[82][84], respectively.

4. Importance of Nickel and Nickel-Oxide Nanoparticles

5. Mechanism of Action of Nickel Nanoparticles

Antibacterial activities of NiNPs are related to nickel ion content which interpenetrate the bacterial cell and reach the surface of the bacterial cell membrane and intracellular milieu. This influx of nickel cations destroys organelles like ribosomes and affects bacterial metabolism. A study of the literature unravels how all of this happens, due to electrostatic attraction and the use of negatively charged intercellular microbial cells and positively charged nickel ions ^[89][90][103,104]. Nanoparticles exhibit great surface activity due to the large surface-to-volume proportion. Exposure of E. coli to NiNPs disrupts membrane morphology and transport. Nickel’s high affinity to sulfur- and phosphor-containing components such as DNA and proteins disrupts DNA replication and causes protein deformation ^[91][105].