Section 4 New Treatments

## **Chapter 7**

## The Ability of Some Inorganic Nanoparticles to Inhibit Some *Staphylococcus* spp.

*Abdalmohaimen Suood, Iman Mahdi and Mahmood Saleh*

#### **Abstract**

In the last decades, antibiotics were used to treat infections caused by some *Staphylococcus* species, especially *Staphylococcus aureus* and *Staphylococcus epidermidis*. The widespread use of antibiotics to treat staphylococcal infections has resulted in an increase in the resistance of bacteria to antibiotics, particularly to beta-lactam antibiotics. In recent years, researchers have been working on developing new antibiotics, despite the fact that they are complex and expensive and carry a number of risks associated with drug toxicity. Using new substances that have good potential against bacterial infection without causing bacteria to become resistant to these substances is currently being researched. More research has been carried out on the effect of silver and copper nanoparticles in neutralizing staphylococcal infection in laboratory studies. The toxic effect of nanoparticles was a concern to scientists, but despite that, the studies *in vivo* found that there was no toxic effect at low doses of nanoparticles on rats. The findings in this field were acceptable to entice researchers to develop these substances.

**Keywords:** *Staphylococcus aureus*, *Staphylococcus epidermidis*, silver, copper, nanoparticles

#### **1. Introduction**

Bacteria belong to prokaryotic organisms, which means they have no clear nucleus such as in eukaryotic organisms. Many bacteria exist as normal flora in or on human skin, and some bacteria are opportunistic and pathogenic to their hosts; Staphylococcal bacteria have a large number of species. The species that are mentioned more than once in scientific reports that cause infections and pathogenicity to their hosts are *S. aureus* and *S. epidermidis* [1, 2]. *S. aureus* is Gram-positive bacteria that causes a variety of diseases. Furthermore, *S. epidermidis* has been identified as a second cause of wound inflammation after *S. aureus* in the last two decades [1]. Chemotherapy (antibiotics) and biological therapy have been used to eliminate the pathogenicity of some bacteria for decades.

Although some of the antibiotics have good results in reducing the pathogenicity of some Staphylococcal bacteria, the problem of resistance has begun to appear, for example, methicillin-resistant *S. aureus* (MRSA). A new agent has been applied to

solve this problem, represented by nanomaterials. Silver and copper nanoparticles showed a nice result against selected pathogen isolates that were resistant to agents of antibiotics [3, 4].

This chapter explores a brief overview of *S. aureus* and *S. epidermidis,* as well as the impact of some nanoparticles in the suppression of their pathogenicity.

#### **2.** *S. aureus*

*S. aureus* produces a purple stain when Gram stain is applied to it, for this reason, it is named Gram-positive bacteria. This species is found mainly as part of the natural microbiota on the skin, gland skin, and infrequently in the mucous membrane of birds and mammals. *S. aureus* becomes more pathogenic than other Staphylococcal species, such as *S. epidermidis*, when suitable habitat elements are provided. *S. aureus*, which is cited in numerous scientific studies, causes a variety of diseases [5]. The virulence factors that make this species more ferocious against its host are the source of its illnesses. The use of antibiotics to treat pathogenic bacteria has increased over the last 10 years. Therefore, *S. aureus* has become increasingly resistant to antibiotics, as seen by the MRSA strain.

#### **3.** *S. epidermidis*

Another Gram-positive bacteria species is *S. epidermidis*. *S. epidermidis* belongs to coagulase-negative Staphylococci (CoNS), which means it lacks the enzyme coagulase, compared with *S. aureus*, which has the enzyme coagulase [6]. The usual inhabitant can also be found in human skin and mucosal membranes. *S. epidermidis* is infrequently known to cause infections in normal humans, but infections of this species are becoming more common in susceptible patients, particularly long-term hospital patients or patients with implanted foreign bodies [7, 8]. *S. epidermidis* has the ability to attach and develop on polymer surfaces, then produce extracellular slime substances, and finally cause the pathogenesis of polymer-associated illnesses [9]. The slime substance clearly guards the imbedded Staphylococci against antibiotics. Frígols et al. [10] have found that methicillin-resistant *S. epidermidis* (MRSE) is a common cause of infectious keratitis caused by *S. epidermidis* and shows a high rate of multidrug resistance.

### **4. Glance of nanotechnology**

Nanotechnology is a new science with a short history of knowledge. Nanotechnology applications make revolutions in many fields because nanomaterial characterizations have a huge difference compared with bulk materials [11].  It describes any materials or processes at the nanoscale that are based on biological or biologically inspired molecules, such as nanotechnology devices used in controling and monitoring in medicine. Another example uses nanocarriers loaded with medicine that are used to introduce therapy into pathogen microbes or unusual cells that belong to tissue (cancer therapy) [12]. Nanoparticles are incredibly tiny particles with sizes between 1 and 100 nanometers. Several nanoparticles have

*The Ability of Some Inorganic Nanoparticles to Inhibit Some* Staphylococcus *spp. DOI: http://dx.doi.org/10.5772/intechopen.107928*

been used to test their activity against harmful microbes. Methods to synthesize these particles are divided into three categories, which are biological, chemical, and physical. Inorganic reducing agents are used in nanoparticle syntheses, such as silver and copper nitrate. Numerous inorganic nanoparticles have been employed in numerous scientific articles [13–15]. Among these, silver and copper nanoparticles are two that will be discussed in the subsections that follow.

#### **4.1 Silver nanoparticles**

Silver nanoparticles have attracted interest in the biological field due to their special characteristics, such as size and shape that depend on magnetic, optical, and electrical properties [16]. These characteristics also make it possible to use silver nanoparticles in antimicrobial applications and other medical-related applications. Many biological, chemical, and physical methods have been employed to synthesize and stabilize silver nanoparticles [17]. The popular methods for the production of nanoparticles are chemical approaches. The method using chemical materials almost contains toxic materials. Therefore, chemical methods are considered toxic, not ecofriendly, and expensive ways to synthesize nanoparticles. For this reason, easy and simple methods are required to produce silver nanoparticles without using harmful or expansive materials. Biological or green chemistry has been used in recent years in abundance [18]. Microorganisms or plant extracts are used as reducing agents to inorganic raw materials for nanoproducts [19, 20].

#### *4.1.1 Silver nanoparticles with anti-pathogenic properties*

The problem of resistant pathogen bacteria to antibiotics and the product of another generation of antibiotics is a big challenge to scientists at present. Development of a new generation of antibiotics takes time and is expansive. It is necessary to find another medicine that has stability with activity without resistant pathogen bacteria to it. It is necessary to treat harmful bacteria. Inorganic nanoparticles are a current drug that is hoped to be effective almost immediately. Silver nanoparticles have been widely used as antibacterial agents in the medical field, food storage, textile coatings, and a variety of environmental applications. Silver nanoparticles' antimicrobial qualities have led to their employment in a variety of disciplines including medicine, industry, animal husbandry, packaging, accessories, cosmetics, health, and military applications [21]. The interest in the activity of silver nanoparticles toward the pathogen *S. aureus* has increased in the last 8 years, as shown in **Figure 1**.

The study of the synergetic effect of silver nanoparticles with antibiotics, for example, erythromycin, amoxicillin, penicillin G, clindamycin, and vancomycin against *S. aureus* [23] was another hope. The technique approved its activity against pathogen bacteria *in vitro* (inside laboratory). Due to the perfect results of antibacterial activity of silver nanoparticles combined with some antibiotics *in vitro* assay, these results inspired the researchers to assay this technique *in vivo* tests using animal models (inside the organism's body) [24]. Xu et al. [25] demonstrated the effect of silver nanoparticles combined with vancomycin, rifampin, and other antibiotics used in their study *in vitro* as well as *in vivo* assay. The silver nanoparticles successfully passed assays *in vitro* and *in vivo* and hope to be used for human treatment in the next few years.

Resistance to silver nanoparticles by bacterial cells has been reported. Elbehiry et al. [26] explored the resistance development of *S. aureus* to silver nanoparticles

#### **Figure 1.**

*Increasing publication regarding the activity of silver nanoparticles against the pathogen* Staphylococcus aureus *in recent years [22].*

after multiple generations of *S. aureus*. As well, Panáek et al. [27] demonstrated that after repeated exposure to inhibitor concentrations of silver nanoparticles, Gramnegative bacteria such as *Escherichia coli* develop resistance to silver nanoparticles. This resistance is not concerning due to these phenotypic changes and not genetic changes, which means this factor will not be transported to future generations of bacteria cells. Furthermore, the multiple mechanisms of action of nanoparticles may limit the development of bacterial resistance to nanoparticles.

#### **4.2 Copper nanoparticles**

Finding another nanoparticle with excellent properties at a lower cost is becoming more required nowadays. Copper nanoparticles have been widely used as inexpensive and effective therapeutic for certain harmful bacteria. Therefore, copper nanoparticles could be a useful antibacterial agent in the coming days. Copper nanoparticles are highly reactive due to their high surface-to-volume ratio; this allows them to easily interact with other particles and boost their antibacterial efficiency. Copper nanoparticles have received much interest because of their unique physiochemical properties, surface-to-volume ratio, cheap preparation, and nontoxic preparation. They have many amazing uses in various domains, such as anticancer activity [28], antimicrobial activity [29], antifungal activity [30], catalysts [31], and antioxidant activity [32]. The creation of copper nanoparticles has been described in numerous scientific works using chemical, physical, and biological methods [33]. The biological method uses natural reducing agents that can be found in plant extracts, fungi, and bacteria to convert copper salt into copper nanoparticles [34–36]. A commendable job has been done regarding the production and stability of copper nanoparticles by using biological processes.

#### *4.2.1 Copper nanoparticles as antibiotics for some human pathogen bacteria*

Copper metal is one of the essential elements, especially in most living organisms. The particles of copper in the nanoscale have different properties compared with

*The Ability of Some Inorganic Nanoparticles to Inhibit Some* Staphylococcus *spp. DOI: http://dx.doi.org/10.5772/intechopen.107928*

copper particles and have many applications, one of them is an antibacterial agent. Copper nanoparticles possess better properties as inorganic antibacterial agents relative to other expansive metal nanoparticles such as gold and silver [37]. For instance, the copper nanoparticles recorded higher antibacterial activity relative to silver nanoparticles against some human pathogen bacteria [38].

According to **Figure 2,** copper nanoparticles have received a lot of attention from researchers lately due to their antibacterial action against many pathogens of *S. aureus* [40].

Despite only a few scientific studies examining the efficacy of copper nanoparticles against *Staphylococcus epidermidis* [41, 42], they have revealed potency against this isolate. Consequently, it is a promising medical treatment.

Another strategy has been applied using a solution of antibiotics with copper nanoparticles. Selvarani [43] showed the effect of tetracycline alone against *S. aureus*, recording an inhibition zone at 25.3 mm using the disc diffusion method, but when impregnating the disc of antibiotics with 50 μl of freshly prepared copper nanoparticles, the diameter of the zone of inhibition was increased to 32.6 mm, increasing by 28%. The same study with another antibiotic (Rifampicin) recorded an increase of 13.8% compared with Rifampicin alone. Additionally, Woźniak-Budych et al. [44] investigated the activity of Rifampicin combined with copper nanoparticles toward four bacterial strains, one of those being *S. aureus*, and found a synergic effect of Rifampicin with nanoparticles was a successful way to prevent the development of resistance. Therefore, there is hope through combining inactive antibiotics with some inorganic copper nanoparticles to convert them into active antibiotics. It is another promising solution to the problem of *S. aureus* and *S. epidermidis* antibiotic resistance.

#### **4.3 Mechanism of antibacterial activity of silver and copper nanoparticles toward bacteria**

The antibiotics are categorized according to their specific targets, which makes them safe for human use. Antibiotics' mechanisms of action include five basic mechanisms against bacterial cells, which are inhibition of cell wall synthesis, inhibition of

#### **Figure 2.**

*Increasing publication regarding the activity of copper nanoparticles against the pathogen* Staphylococcus aureus *in recent years [39].*

protein synthesis (translation), alteration of cell membranes, inhibition of nucleic acid synthesis, and finally antimetabolite activity [45]. Silver nanoparticles no longer have a clear mechanism, such as antibiotics against pathogenic bacteria, but many studies have been conducted on their possible mechanisms of antibacterial properties [46–48]. In recent years, silver nanoparticles have been used in many fields, including medicine, air and water purification, and others [49].

The properties of the mechanisms for silver nanoparticles are well described [48]. The nanoparticles of silver that adhere to the surface of the bacterial cell membrane probably disrupt the functions of the cell membrane, such as respiration and substance transport, as well as cell membrane separation from the cell wall partial or complete [50]. The increased stickiness of nanoparticles results in increased destruction permeability capacity and cell division that lead to a fast rate of death for bacteria compared with the low concertation of nanoparticles. The above description includes the hypothesis of silver nanoparticles' mechanism of antibacterial that sticks to cell walls and cell membranes. The silver nanoparticles can pass through the cell wall of bacteria and reach the cell membrane easily because there are pores in the cell wall. However, there is another hypothesis about silver nanoparticles that successfully reach inside bacterial cells. As a result, silver nanoparticles' creation links with phosphorus and sulfur present in cytoplasmic molecules of bacteria, such as DNA, causing the death and destruction of bacteria [51]. Another possible effect of silver nanoparticles is the disruption product of energy compounds (adenosine triphosphate ATP) and the generation of DNA. They then produce reactive oxygen species (ROS), which are considered toxic to bacterial cells [52].

The mode of action of copper nanoparticles toward antibacterial has little information explained. The researcher proposed the mechanism of activity of copper nanoparticles on pathogen bacteria may have a similar mode of action to silver nanoparticles [53]. Schrand et al. [54], it was hypothesized that copper nanoparticles work as antibacterial agents against many bacteria species due to interaction with SH-groups that result in protein denaturation. Copper nanoparticles may have an effect on cell membrane because of their affinity toward the amines and carboxyl groups that are found on the membranes of some bacteria strains [55]. The nanoparticles can enter a cell through the pores in the cell membrane because of their nanoscale size, or get inside bacteria through ion channels and transport proteins in the membrane of bacteria. After copper nanoparticles enter the cell, they may bind to DNA molecules and disturb the structure of the DNA strands, as well as find copper ions inside bacterial cells, which also disturb biochemical processes [56]. Deryabin et al. [57] hypothesized another mechanism, copper nanoparticles may accumulate on the cell of bacteria and diffuse inside the cell, causing oxidative stress that causes the cell of bacteria to die. **Figure 3** depicts all possible mechanisms of action for silver and copper nanoparticles. Due to limited studies discussing the mechanisms of bioactivities of copper nanoparticles against bacteria, the mechanism of action of copper nanoparticles needs more studies about their cytotoxicity and safety to be used as a human medicine agent to treat harmful bacteria.

#### **4.4 The possible toxic effects of silver and copper nanoparticles**

The toxic effects of nanoparticles of silver and copper have been studied. In the study by Nakkala et al. [58], the rats were treated orally with 5 and 10 mg/kg of silver nanoparticles for 28 days. The rat organs, such as liver, lungs, kidney, spleen, heart, testes, and brain, showed no histopathological changes at the end of the test. Elbehiry *The Ability of Some Inorganic Nanoparticles to Inhibit Some* Staphylococcus *spp. DOI: http://dx.doi.org/10.5772/intechopen.107928*

#### **Figure 3.**

*Nanoparticles' possible mechanism of action on and in bacterial cells.*

et al. [26] also studied the toxic effects of silver nanoparticles at 0.25, 0.5, and 1 mg/ kg in the brain, liver, kidneys, heart, and spleen of rats. After 28 days of testing, they did not find any histological changes in the organs of experimental animals. In contrast with the findings of Kim et al. [59], they noted that after feeding the rat with silver nanoparticles for long-term oral administrated concentrations of 30, 300, and 1000 mg/kg, any changes in the weight of the rat body were not recorded, but they noted the accumulated silver nanoparticles in different tissue organs. In addition, Tiwari et al. [60] found that the treated cells of the liver and kidney with high doses of silver nanoparticles at 20 and 40 mg/kg showed abnormal structures of the cell, as well as nanoparticle deposition in the cytoplasm and nuclear membrane of tested orangs at 40 mg/kg concentration.

Doudi and Setorki [61] treated the experimental rats with different concentrations of copper nanoparticles (10, 100, and 300 mg/kg) after they studied the effects on the liver and lungs. The results of their work have been shown to cause structural changes in cells of the liver and lungs at high doses. Another work by Lei et al. [62] took tissue sections from the liver and kidney of rats that were treated with 100 and 200 mg/kg of copper nanoparticles once a day for 5 days. The necrosis in the liver has been noted at 200 mg/kg with structural changes in the kidney, while there was no alteration in the structure of the liver and kidney cells at 100 mg/kg. Wang et al. [63] studied the effects of various concentrations of copper nanoparticles on rats. Their study explored histological alterations in the liver, spleen, and kidney in male and female rats at 1250 and 2500 mg/kg.

The previous studies of the effects of silver and copper nanoparticles on the organs of rats at various doses of nanoparticles above concluded that the high doses showed clear accumulation and toxic effects of nanoparticles *in vivo* studies. While at low doses, there were no histological changes in the rats with safe use. Future work is required to clarify the biological effects of silver and copper nanoparticles using animal models.

#### **5. Conclusions**

The pathogenicity of Staphylococcal, especially *Staphylococcus aureus*, is widespread in nosocomial infections and long hospitality treatment periods between

patients. However, *Staphylococcus epidermidis* has a recent history of pathogenicity with inflammation wounds. The drugs used in the protocol of treatment for bacterial infection are antibiotics. Widespread use of antibiotics produces problems for medical scientists related to resistant bacteria to these drugs. These problems come from transport genes responsible for resistance from honor plasmid to receiving plasmid in bacteria.

The development of a new generation of antibiotics takes time and is expansive at the same time. Using a new drug with excellent bactericide activity is a recent option to solve this problem in the medicine sector. Nanoscience is one of the options selected to solve this challenge. A number of inorganic nanoparticles have been synthesized using biological methods. Silver nanoparticles have been approved for their activity against many pathogens, including *S. aureus* and *S. epidermidis*, depending on several scientific reviews without resistance bacteria to it. The other inorganic nanoparticles, such as copper nanoparticles, have been reviewed, and the activity of copper nanoparticles toward several human pathogens of *S. aureus* and a limited number of *S. epidermidis* has been reviewed.

Antibiotics have a known mechanism of activity against bacteria. In comparison with silver and copper nanoparticles, they have antibacterial activity but no clear mechanism, such as in antibiotics. Four suggested hypotheses about the mechanism of inorganic silver and copper nanoparticles have been discussed. The nanoparticles first adhere and accumulate on the cell walls of bacteria. The second hypothesis suggested transporting the nanoparticles of silver and copper passed through the pore in the cell wall and reached the surface of the cell membrane. Some of the nanoparticles that accumulated on the surface of the cell membrane worked to modify the permeability of the cell membrane and disturb the respiration process in the cell membrane of bacteria, resulting in the entry of harmful materials inside the cell, causing death to bacteria. The nanoparticles that successfully passed the cell membrane using channel of ion exchange or proteins channel or even through the self-membrane of cell because they have tiny small size compared with the size of the membrane reacted with the DNA molecules causing an inhibition of the DNA replication, and because of that, there is no transcription and translation happened. The last hypothesis talked about the creation of reactive oxygen radicals. This product is considered toxic to cells. More investigated studies *in vivo* as animal models need to study the safety of the nanoparticles to use them as drugs.

## **Conflict of interest**

The authors declare no conflict of interest.

*The Ability of Some Inorganic Nanoparticles to Inhibit Some* Staphylococcus *spp. DOI: http://dx.doi.org/10.5772/intechopen.107928*

## **Author details**

Abdalmohaimen Suood1 \*, Iman Mahdi2 and Mahmood Saleh<sup>2</sup>

1 Directorate of Salah al-Din Education, Ministry of Education, Ishaqi, Iraq

2 University of Tikrit, Tikrit, Iraq

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 8**

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

*Enitan Omobolanle Adesanya and Akingbolabo Daniel Ogunlakin*

## **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 communityacquired 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.

**Keywords:** staphylococcal infections, vaccines, medicinal plants

## **1. Introduction**

*Staphylococcus* is a genus in the Bacillales order that belongs to the Staphylococcaceae family. Microscopically, they appear spherical and form grapelike 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

*Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

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 *Enterobacte*r *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 antibacterialresistant 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. Communityacquired 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% [29–31]. 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 [32–34]. 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, 35–38]. 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].

#### *Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

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].

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, 66–69].

#### **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*

*Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

#### **Table 1.**

*Mechanisms of medicinal plants against MRSA bacteria strain growth.*

*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 drugsensitive 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)-2*H*-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-αarabinopyranoside. 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-αarabinopyranoside 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

*Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

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

#### *Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

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 latestage 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 [92–94].

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.

## **Author details**

Enitan Omobolanle Adesanya1 \* and Akingbolabo Daniel Ogunlakin2

1 Faculty of Pharmacy, Department of Pharmacognosy, Olabisi Onabanjo University, Ago Iwoye, Nigeria

2 Phytomedicine, Molecular Toxicology and Computational Biochemistry Research Group, Biochemistry Programmes, Bowen University, Iwo, Nigeria

\*Address all correspondence to<EMAIL_ADDRESS>
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*Potential Use of African Botanicals and Other Compounds in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.108351*

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## *Edited by Jaime Bustos-Martínez and Juan José Valdez-Alarcón*

The study of staphylococci has a long way to go, due to the great significance both for humans and for dairy or companion animals of their large number of virulence factors. Their resistance to antibiotics makes these microorganisms become highly pathogenic species that can cause infections ranging from mild to fatal. Staphylococci, especially *S. aureus* and strains resistant to methicillin (MRSA), are among the most studied microorganisms worldwide. This book covers recent advances in the study of staphylococci. The book is divided into four sections that cover four important events for the study and combat of staphylococci: colonization, epidemiology and pathogenesis, diagnosis, and new treatments. Staphylococci can present a broad spectrum of resistance to antibiotics, which is why their elimination has become difficult. The final section of the book is devoted to new compounds for the fight against staphylococci. We hope that the information contained in this book will be useful for the study and investigation of these medically important microorganisms.

> *Alfonso J. Rodriguez-Morales, Infectious Diseases Series Editor*

Published in London, UK © 2023 IntechOpen © 123dartist / iStock

Staphylococcal Infections - Recent Advances and Perspectives

IntechOpen Series

Infectious Diseases, Volume 17

Staphylococcal Infections

Recent Advances and Perspectives

*Edited by Jaime Bustos-Martínez*

*and Juan José Valdez-Alarcón*