Potential Use of African Botanicals and Other Compounds in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections

Abstract

Infections caused by the group of Staphylococcus bacteria are commonly called Staph infections, and over 30 types of Staphylococcal bacteria exist with Staphylococcus aureus causing about 90% of the infections from the genus. Staphylococcus aureus (S. aureus) is a major cause of both hospital- and community-acquired infections with major concern arising from its strain of species that is resistant to many antibiotics. One of such strain is the Methicillin-resistant Staphylococcus aureus (MRSA) that has been described to be a resistance to methicillin drugs. Another is glycopeptides-resistant emerging from the increased use of glycopeptides drugs. This continuous emergence and spread of new resistant strains of S. aureus is a major challenge which makes the search for novel anti-resistant agents imperative. The development of vaccines from natural and synthetic products is some of the measures being proposed for the protection against the infections. Also, the development of monoclonal or polyclonal antibodies for passive immunization is sought for, and attentions with regard to arriving at successful trials have been directed back to medicinal plant research as an alternative. This review discusses the treatment strategies of MRSA, the antibacterial property of various medicinal plants, and the influence of their active compounds on methicillin-resistant S. aureus (MRSA), as well as to recommend the path to future research in this area.

1. Introduction

Staphylococcus is a genus in the Bacillales order that belongs to the Staphylococcaceae family. Microscopically, they appear spherical and form grape-like clusters. The genus is a Gram-positive bacterium, and their species are facultative anaerobic organisms, meaning they can grow in both aerobic and anaerobic environments. The genus contains approximately 30 species, nine of which have two subspecies, including one three subspecies and the other with four subspecies [1]. Many species in the genus do not cause disease and typically live just on skin and mucous membranes of animals and humans. Staphylococcus species have been identified as nectar-inhabiting microbes and a minor component of the soil microbiome [2]. Among the bacteria in this genus, five are considered potential human pathogens: S. aureus, S. epidermidis, S. saprophiticus, S. haemolyticus, and S. hominis, with the first three species the most common. However, S.aureus is considered as the most dangerous pathogen, and one of the Staphylococcus species is capable of coagulating plasma [3].

2. Types of staphylococcal infections

There are numerous types of infections caused by Staphylococcus bacteria, which are frequently found on the skin or in the nose of many healthy people. These infections are usually harmless or can cause minor skin infections [2]. However, infections can be fatal when bacteria enter the bloodstream, joints, bones, lungs, or heart and are thus regarded to as bloodstream pathogenic bacteria [4]. As a result, a number of otherwise healthy people are developing potentially fatal staphylococcal infections [5]. Although these infections are communicable and can be acquired by sneezing, coughing, or touching an infected wound, many cases occur when an individual comes into contact with contaminated items such as a wet towel, remote control, or door handle. Similarly, direct personal encounter with an infected person can allow the spread of the infection [4]. There have been several staphylococcal infections ranging from skin infections that cause open sores to bloodstream infections widely recognized as bacteremia infestation of the bone to endocarditis, septicaemia an infectious disease of the heart lining, food poisoning, pneumonia, and toxic shock syndrome (TSS) (a life-threatening predicament caused by contaminants from certain kinds of bacteria) [6].

3. Risk factors for staphylococcal infections

Since Staphylococcus bacteria are commensal organisms, anyone can develop a staphylococcal infection. However, some people are at higher risk, including those who have a chronic medical condition including hyperglycemia, cancer, vascular disease, eczema, and lung disease, a compromised immune system such as HIV/AIDS, on medications to prevent organ rejection, or chemotherapy. Likewise, those who have recently had surgery and those who use a catheter, breathing tube, or feeding through tube are susceptible to Staph infection [7]. Those on dialysis and those who use illegal drugs to participate in contact sports are also at high risk [8]. For the latter, the drugs increase the rate of sweating; thus, it encourages skin-to-skin interaction with other people or via device sharing.

3.1 Drug resistance

When an infection occurs, antibiotics are prescribed for treatment based on the type of infection. Such treatments can come in the form of a lotion, ointment, medications (to swallow), or intravenous (IV) injection, while surgery is proposed for bone infectious diseases [4]. Although antibiotics are used, there have been cases where it does not work; hence, we say that the Staphylococcus bacterium has grown resistant to the antibiotics. The different species of Staphylococcus have cases of antibiotic resistance, but widespread prevalence of antibiotic resistance strains are commonly found in the Staphylococcus aureus known as methicillin-resistant Staphylococcus aureus (MRSA) [9].

Staphylococcus aureus has now been confirmed to be resistant to many antimicrobial agents over the last few decades, but it has recently become tolerant to daptomycin and linezolid, two of the most recent lines of therapies [10]. Staphylococcus aureus bacteria is a member of the ESKAPE pathogens comprising of Enterococcus faecium, S. aureus, Klebsiella spp., Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are capable of “escaping” the biocidal action of antibiotics and jointly representing new paradigms in pathogenesis, transmission, and resistance group of bacteria, all of which have multidrug resistance profiles [11]. Although MRSA infections have decreased in the United States, Europe, Canada, and South Africa, an increase has been observed in some regions, including sub-Saharan Africa, raising public health concerns [12].

3.2 Mechanisms and site of resistance

There are several antibacterial resistance molecular mechanisms. One example is intrinsic antibacterial resistance, which can be found in the genetic composition of bacterial strains. For example, an antibiotic target may be missing from the bacterial genome but acquired resistance from a chromosomal mutation or the acquirement of extra-chromosomal DNA [13]. Furthermore, antibacterial-producing bacteria have developed defense mechanisms that have been found to be similar to antibacterial-resistant strains and may have been transferred to them. Furthermore, antibacterial resistance is frequently spread via vertical transmission of gene mutation during growth and genetic recombination of DNA via horizontal genetic transfer [14]. Antibacterial resistance genes, for example, can be interchanged among various bacterial strains or species through plasmids carrying these resistant gene [15]. Plasmids containing multiple resistance genes can bestow resistance to various antibacterial agents [15]. Also, cross-resistance to the many antibacterial could indeed arise if a resistance mechanism encrypted by a specific gene expresses resistance to even more than one antibacterial chemical agent [15, 16].

Antibacterial-resistant species, dubbed “superbugs,” are now contributing to the onset of diseases that were previously under control. Newly emerging bacterial strains usually cause tuberculosis which are tolerant to subsequently good antimicrobial therapies, for example, pose numerous therapeutic challenges, as does New Delhi metallo-β-lactamase-1 (NDM-1), a newly identified enzyme that transmits bacterial resistance to a wide spectrum of beta-lactam antibacterial agents [17]. According to a report published by the United Kingdom’s Health Protection Agency, “thus many isolates with NDM-1 enzyme are tolerant to all conventional intravenous antibiotics prescribed to treat severe infections” [18].

3.3 The management of staphylococcal infections

Regardless of the fact that several novel antimicrobial drugs have just been developed, resistance rate to them has managed to increase and has become serious challenge as we run out of candidates’ drug. Antimicrobial resistance issues are being addressed both in healthcare and community configurations, necessitating a multidisciplinary approach involving many different collaborators across the care continuum. For instance, in a survey report by Okwu et al. [19], 18–33 percent of the total S. aureus-infected patients went on to develop MRSA infections. Community-acquired methicillin-resistant Staphylococcus aureus strains (CA-MRSA) are also becoming more common in hospital-onset MRSA infections. As stated by the Centers for Disease Control and Prevention (CDC), antibiotic resistance causes more than 2 million ailments and 23,000 deaths in the United States each year [20].

Methicillin-resistant Staphylococcus aureus has gained worldwide popularity, and its incidence has risen in both care services and community-based settings. MRSA prevalence varied by country, for example, 0.4% through Sweden [21]; 25% in Western India to 50% through Southern India [22]; 33%–43% in Nigeria [19]; and 37–56% in Greece, Portugal, and Romania in 2014 [23]. Also, MRSA has been found in hospitals all over the world, with rates exceeding 50% in Asia, Malta, North and South America, and Europe [24, 25]. Its prevalence rates varied due to various prevalence factors including geographic location and health service capacity to run infection control programs [26]. Akanbi and Mbe [27] found vancomycin-resistant Staphylococcus aureus (VRSA) in clinical isolates ranging from 0% to 6% in southern Nigeria, and 57.7% across Zaria, the northern part of Nigeria.

Likewise, vancomycin resistance was found in 1.4% of S. aureus isolates through Southern India [28]. Other countries, including Australia, Korea, Hong Kong, Scotland, Israel, Thailand, and South Africa, have reported S. aureus with reduced vancomycin sensitivity, with prevalence ranging from 0 to 74% [29, 30, 31]. Despite the frequent use of vancomycin in the treatment of pathogens, numerous researchers have documented vancomycin intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) occurrences [32, 33, 34]. Teicoplanin, daptomycin, linezolid, and other costly drugs are currently used to treat bacteria with low vancomycin sensitivity. However, global resistance to these drugs has been identified [22, 35, 36, 37, 38]. The MRSA infection remains a significant issue all over the globe and also a therapeutic challenge due to the scarcity and high cost of antibacterial agents. The increasing existence of MRSA infections, changing antibiotic resistance, and involvement in hospital and community infections have an influence on the use and treatment outcomes of previously existing anti-infective compounds [39].

Plants have been used for centuries to treat illnesses and diseases. Plant extracts are being studied as medicines, because several studies have shown that their crude extracts possess antimicrobial effect and could be excellent substitutes for current antibiotics. Recent published reports suggest that medicinal plants with anti-MRSA activity may be taken into account as medication of MRSA infections [36, 40].

3.4 Medicinal plants and staphylococcal infections

Natural products, such as medicinal herbs, have contributed significantly to human wellbeing and drug development. Ethno-medicinal plants have the possibility to be effective therapeutically. Over 80% of patients in many developing countries, including Nigeria, treat contagious diseases with home-made herbal remedies. Regardless of whether Western medicine is available in certain localities, medicinal plants are still extensively utilized because of their effectiveness, relevance, and low cost. Although all parts of the plant are utilized in traditional therapies and can therefore act as lead compounds, they are also promising sources of novel pharmaceutical substances. Recent years have seen a substantial growth in the utilization of natural remedies for human wellbeing and as blueprints for developing newer beneficial pharmaceuticals around the world [41].

The emergence of multidrug-resistant pathogenic organisms associated with the overuse and misuse of antibacterial agents has compelled the World Health Organization (WHO) to acknowledge and make known the pressing need to find unique antibiotic and/or innovative techniques to combat the global threat posed by them [42]. This has resulted in a resurgence of research in traditional medicines [43]. Table 1 shows the various mechanisms of medicinal plants and their bioactive compounds. Their mechanisms of action includes increased cell wall membrane penetrability, downregulation of efflux pump systems, reconfiguration of the active site or enzymatic ruin, and modification of bacterial enzymes [61].

Plant	Part/solvent for extraction	Dose (MIC)	Active constituents	Mode of action	Reference
Allium sativum	Rhizhome			Inhibition of cell wall synthesis; Inhibition of cell membrane function	[44]
Pimenta dioica	Essential oil			Inhibition of MRSA growth	[45]
Aloe vera	Leaf exudate			inhibition of protein synthesis	[44]
Alpinia galangal	Rhizhome			Inhibition of cell wall synthesis; Inhibition of cell membrane function	[44]
Cinnamomum camphora	Essential oil		Camphor	Inhibiting MRSA growth	[45]
Canarium odontophyllum	Leaves/methanol; Leaves/acetone	312.5 𝜇g/mL; 156.25 𝜇g/m	Saponin	Bactericidal action	[46]
Cinnamomum zeylanicum	Essential oil			Inhibition of MRSA growth	[45]
Salvia sclarea	Essential oil			Inhibition of MRSA growth	[45]
Syzygium aromaticum	Essential oil			Inhibition of MRSA growth	[45]
Curcuma domestica	Rhizhome			Inhibition of cell membrane function; inhibition of protein synthesis	[44]
Curcuma xanthorrhiza	Rhizhome			Inhibition of cell membrane function	[44]
Citrus paradise	Essential oil			Inhibition of MRSA growth	[45]
Cymbopogon citratus	Essential oil			Inhibition of MRSA growth	[45]
Lippa citriodora	Essential oil	55 μl/ml		Cytotoxicity	[47]
Phoenix dactylifera	Seed/ Nanoparticles of aqueous extract	0.67 ± 0.94 μg/ml		Electrostatic attraction between positively charged AgNPs and negatively charged teichoic acid in MRSA cell membrane results in an increase in membrane fluidity and, eventually, destabilization and depletion of intracellular components.	[48]
Piper bettle	Leaves			Inhibition of cell membrane function	[44]
Plectranthus amboinicus	Leaves/hydroalcoholic extract	18.7–9.3 mg/mL	Carvacrol	Modification of the constitution to increase the fluidity of the cell membrane	[49, 50, 51]
Quercus infectoria	Galls/methanol	0.625 mg/mL		Post-antibiotic effect; destruction of bacterial cell wall.	[52]
	Galls/acetone	0.3125 mg/mL
Rhazya stricta	Leaves/aqueous			Bactericidal action	[53]
Sambucus nigra	Flower or berry/water		Tannins (derivatives of gallic acid, hydroxycinnamic acid, caffeic acid) and terpenes		[54]
Syzygium polyanthum	Leaves			Inhibition of cell membrane function; inhibition of cell wall synthesis	[44]
Thymus vulgaris	Essential oil			Inhibition of MRSA growth	[45]
Gaultheria procumbens	Essential oil			Inhibition of MRSA growth	[45]
Zingiber officinale	Rhizhome			Inhibition of cell membrane function	[44]
Eleutherine Americana	Bulb	0.78 μg/mL	Eleucanainones A	Downregulation of basal expression of agrA, cidA, icaA, and sarA in methicillin-resistant S. aureus	[55]
		3.12 μg/mL	Eleucanainones B	Bactericidal action
Anethum graveolens	Essential oil		α-phellandrene, p-cymene and carvone	Topical administration on the MRSA-infected wound in BALB/c male mice significantly elevates Bcl-2 expression which then triggers cellular proliferation.	[56]
Boswellia papyrifera	Oleo-gum; resin/methanol	62.5 to 500 μg/ml		Bactericidal action	[57]
Commiphora molmol	oleo-gum; resin/methanol	31.25 and 250 μg/m		Bactericidal action	[57]
Garcinia mangostana	Ethanol	0.05–0.4 mg/mL		Bactericidal action	[58]
Punica granatum	Ethanol	0.2–0.4 mg/mL		Bactericidal action	[58]
Quercus infectori	Ethanol	0.2–0.4 mg/mL		Bactericidal action	[58]
Glycyrrhiza glabra	Rhizomes/ethanol	50–100 μg/mL	Isoliquiritigenin	Drug resistance reversal effect	[59]
			Liquiritigenin	Drug resistance reversal effect
Cordia latifolia	Methanol			Anti-MRSA effect	[60]
Thymus vulgaris	Methanol			Anti-MRSA effect	[60]

Table 1.

Mechanisms of medicinal plants against MRSA bacteria strain growth.

Several studies have demonstrated that several phytoconstituents possess antibacterial effect against MRSA. On the tested MRSA strains, the plants’ minimum inhibitory levels (MICs) varied widely from 1.25 g/mL to 6.30 mg/mL. Some medicinal herbs had minimum inhibitory concentration of 1.0 mg/mL, whereas few herbs had MIC values that were higher than 1.0 mg/mL and much less than 8.0 mg/mL. Extracts with minimum inhibitory concentration less than 8 mg/mL are broadly acknowledged to have antibacterial effects, whereas those with values less than 1 mg/mL have been classified as exceptional [41, 62].

3.5 Plants’ secondary metabolites and treatment of staphylococcal infection

Botanicals are good source of different classes of phytochemicals. Plants produce phytoconstituents, also referred to as secondary metabolites, as natural biological agents in response to external and abiotic stresses. They are essential for the survival and defense of plants. Polyphenols, alkaloids, steroids, essential oils, saponins, as well as other compounds are among them. They possess antimutagenic, antitumor, free radical scavenging, antiseptic, and anti-inflammatory properties, which contribute to plants’ pharmacological potency [63].

Ethanol and methanol have been the most commonly used solvents for isolation and purification of anti-MRSA molecules from medicinal herbs. This is because alcoholic extracts have a stronger antibacterial property than aqueous extracts. Ethanolic extracts had already been discovered to have stronger antimicrobial properties than aqueous extracts due to the existence of more polyphenols. Ethanol is more effective at breaking down cell membranes and seeds, enabling polyphenols to be released from cells. Another enzyme, polyphenol oxidase, which degrades polyphenols in aqueous extracts, is rendered ineffective in both methanol and ethanol. Additionally, water is an excellent medium for the growth of microorganisms than alcohol [64].

Despite being more ionic than ethanol, methanol is not commonly used in plant extraction because of its cytotoxic nature, which might lead to false-positive findings [65]. The pharmacological influences of these botanicals and their constituents could be utilized in drug development [63]. The phytochemicals in these plants are responsible for their antibacterial (including anti-MRSA) activity through several mechanisms. For example, flavonoids form complex ions with bacterial cell membrane, extracellular proteins, and soluble proteins, meanwhile tannins restrict microbial adhesions, enzymes, as well as cell encircling proteins (Table 1) [58, 66, 67, 68, 69].

3.6 African medicinal plants’ efficacy against staphylococcal infections

Six Nigerian medicinal plants, Bambara (Terminalia avicennioides), Bushveld peacock-berry (Phylantus discoideus), Bridelia (Bridella ferruginea), billygoat-weed (Ageratum conyzoides), basil (Ocimum gratissimum), and copperleaf (Acalypha wilkesiana), were tested in vitro for anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. Water and ethanol extracts of T. avicennioides, P. discoideus, O. gratissimum, and A. wilkesiana were both effective against MRSA. The ethanol extracts of these plants have MICs of 18.2 to 24.0 μg/mL and Minimum Bactericidal Concentrations (MBCs) of 30.4 to 37.0 μg/mL. In contrast, the MIC ranges for B. ferruginea and A. conyzoides ethanol and water extracts were 30.6 to 43.0 μg/mL as well as 55.4 to 71.0 μg/mL, respectively. The MBC values were higher in the two plants. The concentrations in this study were too high to be considered active. Anthraquinones were found in trace amounts in these four active plants [70].

Ethanol extracts of Melianthus comosus, Melianthus major, Dodonaea viscosa var. angustifolia, and Withania somnifera were found to be effective against both drug-sensitive and drug-resistant S. aureus. The minimum inhibitory concentrations for these plants ranged from 0.391 to 1.56 mg/mL. The XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) method was used to test the cytotoxicity of all these plants’ ethyl alcohol extracts on Vero cells. M. major showed a 50% inhibitory activity (IC₅₀) of 52.76 g/mL and was therefore chosen for bioactive principle discovery. Two flavonoids were isolated from the leaves using column chromatography: quercetin 3-O-β-galactoside-6-gallate and kaempferol 3-O-α-arabinopyranoside. These molecules were discovered for the first time in this plant. These flavonoids also do not have antibacterial effect against the methicillin-sensitive strain of S. aureus at the highest concentration (500 g/mL). The antibacterial effect of M. major ethanolic extract observed in this research could be linked to the synergistic effects of the extract’s quercetin 3-O-β-galactoside-6-gallate and kaempferol 3-O-α-arabinopyranoside and/or biomolecules not extracted in this study [71].

Five Nigerian plants mentioned as local antimicrobial agents, Ocimum lamiifolium, Rosmarinus officinalis, Catharanthus roseus, Azadirachta indica, as well as Moringa stenopetala [41, 72, 73], were evaluated in vitro against a panel of seven biofilm-forming MRSA. The medicinal plants’ leaves extract, obtained by extraction with polar solvents of varying polarity, as well as the crude extracts had been evaluated for antimicrobial potential via well diffusion technique. The broth dilution method was employed to calculate the minimal inhibitory levels (MICs) and lowest bactericidal concentration levels (MBC) of extracts against MRSA. Furthermore, most efficacious plant extract was evaluated for anti-biofilm activity. Three of the five studied plants which displayed favorable antimicrobial property include M. stenopetala, R. officinalis, as well as O. lamifolium, according to the findings. Nonpolar solvents extracted antimicrobials effectively than organic solvents with medium and high polarity. This same crude ethanolic extract from M. stenopetala demonstrated the greatest range and rank of activity. Based on the MIC/MBC ratio, the ethanol extract of M. stenopetala had been found to be bacteriostatic. M. stenopetala extract strongly suppressed MRSA development inside the preformed biofilm matrix, according to the anti-biofilm assay [74].

Aspilia mossambicensis, Ocimum gratissimum, and Toddalia asiatica were identified and tested for bioactive antibacterial property. Hexane, ethyl acetate and methanol extract yields varied from 0.5% for Ocimum gratissimum stem bark ethyl acetate extract to 2.7% for Toddalia asiatica root bark methanolic extracts. The extracts were evaluated for in vitro experiments against Gram-positive-resistant Staphylococcus aureus (MRSA) using the disk diffusion method. Methanol extract of Asiatica stem bark had the maximum activity against methicillin-resistant S. aureus (15 mm diameter zone of inhibition). Preliminary phytochemical screening revealed the presence of the large percentage of alkaloids, polyphenols, steroids, and amines. By bioautographic selection, the organisms displayed antibacterial effect against methicillin-resistant Staphylococcus aureus (0.3125 mg/mL), which directly compared to the standard antibiotic gentamycin (0.5 mg/mL). These findings corroborate the ethno-medicinal utilization Toddalia asiatica, a Kenyan folkloric medicine, for bacterial-related conditions [75].

Sharquie et al. [76] studied the antibacterial effects of crude black tea (Thea assamica) treatments. Tea extracts were mixed into a 1% aqueous moisturizer (Group 1) and a 5% petroleum jelly base (Group 2), which were applied three to four times per day. Relieve rates in all these groups were compared to groups receiving framycetin as well as gramicidin cream (Group 3) or oral cefalixin (Group 4). The 5% green tea was just as efficacious as antibiotic treatments (cure rates of 81.3%, 72.2%, and 78.6% in groups 1–4, respectively). The cure rate in Group 1 was 37.5%. Regardless of the fact that sample size for this research seemed to be large, the number of patients in each treatment group was small. Furthermore, because the respondents were not designated randomly, this study was limited.

Another clinical study matched the administration of 4% tea tree oil (TTO) nasopharyngeal ointment and 5% TTO shower gel (intervention) to a conventional 2% mupirocin nasopharyngeal cream and triclosan body wash (routine) for the eradication of methicillin-resistant Staphylococcus aureus (MRSA). Thirty in-patients, contaminated or colonized with MRSA, were randomly assigned to receive TTO or conventional routine care for a maximum of 3 days. Infected patients received intravenous vancomycin as well, and then all participants were checked for MRSA carriage 48 as well as 96 hours after discontinuing topical treatment. Only 18 patients completed the trial. The intervention group cleared more infections than the healthy controls (5/8 versus 2/10). The intervention group included two patients who had been treated for 34 days: one managed to recover from the pathogen and the other patient remained chronically colonized. The group differences were not statistically relevant. This experiment was too small to yield a conclusive result [77].

4. Synergistic effect of synthetic and natural drugs for MRSA treatment

A novel strategy against antibiotic-resistant bacteria, such as MRSA, is synergistic or combination therapy. Plant extracts combined with common antibiotics show promising results in the treatment of MRSA infections. The microdilution method, also known as the checkerboard method, aids in determining the antibacterial interplay between natural and synthetic compounds. The synergistic combination of gentamycin and C. esculenta aqueous leaf extracts demonstrated antibacterial property against MRSA [78]. Blesson et al. [78] found that the phytochemicals in the leaf extracts bind to the MRSA cell wall and increase cell wall permeability as well as increasing the rate at which antibiotics enter MRSA. A synergistic relationship among Alternathera brasiliensis n-hexane fraction as well as erythromycin, ampicillin, and ciprofloxacin was also reported, with fractional inhibitory index (FIC) value varying from 0.208 to 0.375 [79]. Tomatidine, a steroidal alkaloid synthesized by solanaceous plants, possesses powerful and effective antibacterial properties against S. aureus either alone or in combination with aminoglycosides [80].

Piperine, biologically active substance present in pepper, has been shown to have excellent antibacterial properties against MRSA infections when combined with gentamycin [81]. Synergism, or the combination of drugs, is a novel concept in drug development and the treatment of drug-resistant bacteria. The combined action of drugs outperforms the individual actions of the medications. As a result, this method can be used to discover new and efficient drugs against resistant bacteria. In summary, herbal extracts combined with antibiotics such as quinolones, β-lactams, aminoglycosides, tetracyclines, and glycopeptides could greatly enhance antibacterial effects, reduce therapeutic dose, reduce adverse effects, and reverse MRSA resistance. As a result, botanicals coupled with antibiotics could be a beneficial MRSA treatment strategy [82].

5. Vaccines for MRSA treatment

MRSA’s rising antibiotic resistance profile suggests that new interventions such as vaccines and antibiotics are required. There is precedent for developing effective and affordable bacterial vaccines, which aim at single antigens or toxins, specifically capsular polysaccharides. The implementation of these innovations to S. aureus is disrupted by the bacterium’s complex pathogenic mechanisms. Because S. aureus can be found in the normal human flora, it has developed a variety of methods to colonize and evade host immune system, such as polymorphic expression of specific proteins and the release of redundant bacterial pathogens [83, 84]. Animal models, as well as in vitro and ex vivo models, are used in translational science studies to assess vaccine candidates’ efficacy. Although several vaccine candidates demonstrated potential in preclinical testing in a variety of in vivo models, those that have advanced to late-stage drug trials have been unable to demonstrate efficacy in human trials [85, 86].

Two different vaccines were discovered [87]. StaphVAX is a bivalent polysaccharide and protein-conjugated vaccine that targets S. aureus capsular polysaccharide varieties 5 and 8 (CP5 and CP8) that are associated with roughly 80% of S. aureus. In two Phase III trials, the candidate was evaluated to avert bacteremia in end-stage renal dialysis victims during 3 to 54 weeks following immunization. Bacteremia was lowered by 57% during the initial 40 weeks, but potency declined to 26% during week 54 [88]. A conclusive Phase III study of 3600 hemodialysis patients evaluated for bacteremia found no significant difference between vaccinated and placebo controls. The vaccine-induced functional antibody titers throughout this second follow-up Phase III study are yet to be made public. The major reason for the failure of the second trial is currently being credited to production discrepancies among various vaccine lots used in the two trials [89]. Therefore, the candidate’s development was halted. Another candidate, V710, induces immunity against the cell wall-anchored iron scavenger protein IsdB and was tested in a Phase III randomized controlled experiment involving approximately 8000 adults undergoing cardiac surgery. An interim analysis revealed a substantial increase in mortality caused by S. aureus infection, as well as a considerably higher level of other adverse effects [90].

Passive immunization strategies based on polyclonal as well as monoclonal antibodies (mAbs) were developed for individuals who are immunocompromised and unable to install an independent, robust immune response, as well as those who are at instantaneous threat of infection and do not have time for an active immunization to work properly. Five antibody candidates were already developed and tested in late-stage clinical trials, but none have shown efficacy [91].

Monoclonal antibodies, chemotherapy drugs, and centyrins are being designed in addition to bacteriophages. A number of these approaches have already been examined in humans, and the results have been promising. The attention has concentrated on developing a prophylactic product which might protect against potentially fatal S. aureus infections, although it is anticipated that such a vaccine will also protect against other S. aureus infections, including more frequently occurring infections of the skin and tissues [92, 93, 94].

Immune responses that safeguard against invasive S. aureus infections, along with host genetic factors as well as bacterial evasion mechanisms, are critical considerations for the continued development of safe and effective vaccines as well as immunotherapies against invasive S. aureus infections among humans [95]. Discussion on the significance of developing novel vaccine regimens that evoke effective cellular and humoral immune responses is common. This determines that enrolling vaccines in clinical trials provides the highest probability of success in addressing MRSA infections, and a better understanding of the synergy of immunotherapies, antibiotics, and vaccines could indeed aid in the design of future clinical trials [93].

6. Conclusion

Due to the poor prognosis and high cost of treatment associated with this infectious disease, MRSA infections are an increasing challenge for human society. Most antibiotics on the market are becoming less effective against bacterial resistance, particularly MRSA. Thus, new strategies for treating MRSA infections are required. Future MRSA infection treatment methods may include the following features: nanocarriers with a large surface area for targeted delivery of antibiotics with low inhibitory concentrations, design and implementation of antibody-based pharmacological agent therapies for the management of severe MRSA infections, multidrug approaches for handling drug-resistant pathogenic bacteria such as pharmaceutical chemicals, artificial and herbal drugs, and natural medicines, and breakage of MRSA biofilms using an appropriate targeting carrier system and biotic drugs.