Microsoft Word - 11402 NSB Zeouk 2023.03.16.docx Received: 05 Dec 2022. Received in revised form: 02 Feb 2023. Accepted: 07 Mar 2023. Published online: 16 Mar 2023. From Volume 13, Issue 1, 2021, Notulae Scientia Biologicae journal uses article numbers in place of the traditional method of continuous pagination through the volume. The journal will continue to appear quarterly, as before, with four annual numbers. SHSTSHSTSHSTSHST Horticulture and ForestryHorticulture and ForestryHorticulture and ForestryHorticulture and Forestry Society of TransylvaniaSociety of TransylvaniaSociety of TransylvaniaSociety of Transylvania Zeouk I (2023) Notulae Scientia BiologicaeNotulae Scientia BiologicaeNotulae Scientia BiologicaeNotulae Scientia Biologicae Volume 15, Issue 1, Article number 11402 DOI:10.15835/nsb15111402 ReReReReviewviewviewview ArticleArticleArticleArticle.... NSBNSBNSBNSB Notulae Scientia Notulae Scientia Notulae Scientia Notulae Scientia BiologicaeBiologicaeBiologicaeBiologicae From skin infection to invasive diseases: A descriptive review of From skin infection to invasive diseases: A descriptive review of From skin infection to invasive diseases: A descriptive review of From skin infection to invasive diseases: A descriptive review of Staphylococcus aureusStaphylococcus aureusStaphylococcus aureusStaphylococcus aureus, focusing on Panton, focusing on Panton, focusing on Panton, focusing on Panton----Valentine leucocidin and Valentine leucocidin and Valentine leucocidin and Valentine leucocidin and methicillinmethicillinmethicillinmethicillin----resistant strainsresistant strainsresistant strainsresistant strains Ikrame ZEOUK National Agency of Medicinal and Aromatic Plants, Laboratory of Pharmaceutical Industry, Taounate 34025, Morocco; ikramezeouk20@gmail.com AbstractAbstractAbstractAbstract Despite advances in scientific research, Staphylococccus aureus remains a pyogenic and toxigenic bacterium involved in different infections, it endowed with the capacity to infect several biotopes and cause a wide range of infections ranging from skin diseases to other serious pathologies such as pneumonia, meningitis, sepsis, osteomyelitis and infectious endocarditis. Moreover, the emergence of resistant strains constitutes a serious public health problem. Thus, the development of new active compounds from natural sources such as medicinal plants is urgently needed. To this end, the aim of our review was to describe the state of art of infections caused by S. aureus, its pathogenesis, treatment and to provide a synthesis about studies reporting a bio guided isolation of most promising compounds selected for their anti-staphylococcal activity. Keywords:Keywords:Keywords:Keywords: bio guided fractionation; natural products; resistance; Staphylococcus aureus IntroductionIntroductionIntroductionIntroduction The emergence of antibiotic resistance constitutes a serious public health problem. Predictive models have estimated that by 2050, antimicrobial resistance will be the main cause of global death with more than 10 million deaths per year, including around 5 million in Asia, 4 million in Africa, 400.000 in Europe and 300.000 in North America (O’Neill, 2014). The additional cost attributed to antibiotic resistance will increase to 1.5 billion euros (EUR-RC, 2011) in Europe, and in the United States it would be around 55 billion $ (CDC, 2013). The World Health Organization (WHO) has sounded the alarm on the consequences of antibiotic resistance, thus it has placed a global plan action that defines several objectives mainly the development of alternative treatment (OMS, 2016). However, the problem of resistance persists and in 2020 the same organization has declared reemergence of resistant microorganisms and has insisted on the development of new therapeutic molecules (OMS, 2022). Staphylococcus aureus is among the pathogens resistant to treatment, it is an opportunistic and cosmopolitan bacterium that colonizes the skin and mucous membranes of humans. Within this species there are toxigenic variants such as those expressing the Panton-Valentine leucocidin toxin (PVL) which aggravates the pathology and make S. aureus more toxicogenic (Nakaminami et al., 2020; https://www.notulaebiologicae.ro/index.php/nsb/index Zeouk I (2023). Not Sci Biol 15(1):11402 2 Petraitiene et al., 2020). S. aureus causes a major public health problem despite advances in scientific research, it endowed with the capacity to infect several biotopes and cause a wide range of infections ranging from skin diseases to other serious pathologies such as pneumonia (Grousd et al., 2019), meningitis (Aguilar et al., 2010), sepsis (Bawazir and Mustafa, 2020), osteomyelitis (Weiss et al., 2020), and infectious endocarditis (Selton-Suty et al., 2012). Transmission of S. aureus is both community-based and nosocomial (Chow et al., 2020). In addition, strains of S. aureus have developed multidrug resistance to different families of antibiotics. Today, more than 90% of S. aureus strains produce a penicillinase that limits the action of beta-lactams. Moreover, methicillin, the first semi-synthetic penicillin not susceptible to penicillinases, quickly disappointed the medical world with the emergence of strains resistant to methicillin (MRSA). In 2019, WHO has developed a new indicator of antimicrobial resistance to track the frequency of sepsis caused by MRSA and the median rate reported by 25 countries was 12.11% (OMS, 2022). In fact, the treatment of MRSA is based on glycopeptides (vancomycin). However, less susceptible strains to glycopeptides have been isolated. These isolates are called VISA (vancomycin-intermediate S. aureus), or more generally GISA (glycopeptide-intermediate S. aureus). Among the newest antibiotic on the market, linezolid (Zyvox), it was introduced to the North American market in 2000. As early as 2001, cases of MRSA resistant to linezolid have been reported (Tsiodras et al., 2001; Rouard et al., 2018). Faced with the emergence of resistance to current antibiotics, strategies are now in place to renew therapeutic biomolecules. Pharmaceutical companies have turned away from natural products to synthetic chemistry. Thus, tens of billions of dollars have been invested in research and development (R&D), however, these new methods of discovering bioactive molecules seem to have reached certain limits (Gershell and Atkins, 2003; Butler, 2004), which may explain the interest in researching new compounds from natural sources such as medicinal plants that are endowed with a secretion of different secondary metabolites (Bérubé-Gagnon, 2006). The aim of the present review was to describe the state of art of infections caused by S. aureus, its pathogenesis, treatment and to provide a synthesis about studies reporting a bioguided isolation of most promising compounds selected for their antistaphylococcal activity. Staphylococcus aureusStaphylococcus aureusStaphylococcus aureusStaphylococcus aureus The essential reservoir for S. aureus is humans where it lives mainly in the commensal state in moist skin areas (perineum, armpits), mucous membranes and nasal cavities (Freeman-Cook and Cook, 2006). However, these bacteria can become formidable pathogens, after an alteration of the normal skin architecture, an invasive infection could be induced (Archer, 1998). The mode of transmission of Staphylococcus spp. is broader. In other words, there is not a definite cycle of transmission. Air, dust, bedding, blankets, medical equipment, food, and hands are all disseminators of S. aureus emphasizing intra- and human-to-human transmission (Robinson et al., 2019). It is now accepted that S. aureus is one of the most dangerous bacteria transmitted by both community and nosocomial ways, leading to the spread of many serious infections difficult to treat. Clinical manifestationsClinical manifestationsClinical manifestationsClinical manifestations Infections caused by S. aureus can range from skin infections, which are easy to treat, to other invasive pathologies, which are much more difficult to treat or even fatal. S. aureus can infect the skin, respiratory, digestive, urinary and reproductive tracts and can cause serious infections of the heart and bones (Figure 1). Zeouk I (2023). Not Sci Biol 15(1):11402 3 Figure Figure Figure Figure 1111. Skin colonization by Staphylococcus aureus and the resulting infections (By Zeouk, 2022) Skin infections Skin infections Skin infections Skin infections According to Moran et al. (2006), S. aureus is responsible of 76% of skin and soft tissue infections (Moran et al., 2006b). The main skin infections caused by S. aureus include among others impetigo, folliculitis, boil, and skin abscess (Figure 2). Figure 2. Figure 2. Figure 2. Figure 2. Common skin infections caused by S. aureus: A, Impetigo ; B, Folliculitis (Selk and Wood, 2019); C, Boil; D, Skin abscess Zeouk I (2023). Not Sci Biol 15(1):11402 4 The clinical profile of these infections is different; Impetigo is manifested as pustules, vesicles, or delicate bubbles at the superficial level, most often around the mouth or nose, on the chin or behind the ears. It can also affect the trunk, buttocks, or hands. These lesions quickly become inflamed and form honey-colored scabs (Figure 2, A). It is a contagious infection that affects mainly children, but also adults with immune deficiency (Lawrence and Nopper, 2012). Folliculitis begins as small papules, with a pustule centered by a hair associated with perifollicular erythema (Figure 2, B). All parts of the body can be affected, such as the thighs, perineum, arms, back, and eyelid (Selk and Wood, 2019). The deep and necrotizing form of folliculitis with involvement of the pilosebaceous follicle in its entirety, is called a boil (Figure 2, C) which is manifested as a painful inflammatory papule or nodule centered around a pustule (Del Giudice, 2020). The boil looks similar to a skin abscess (Figure 2, D) which is also presented as a nodule or an erythematous mass, sometimes with a central pustule and spontaneous drainage of pus, but which does not have a privileged location (Kobayashi et al., 2015). Thus, Del Giudice (2020) has insisted on considering skin infections caused by S. aureus as a complex group of diseases with a very varied clinical spectrum. Moreover, skin abscesses are the most common and dangerous manifestation of S. aureus, because when they are pyogenic, they can develop in deeper tissues like the underlying muscles, then bacteria can spread to form abscesses throughout the internal organ system (Kobayashi et al., 2015). In a recent retrospective study, Rochet et al. (2020) have shown that the rate of patients visits for skin abscesses in the emergency department has increased significantly and that S. aureus was the pathogen involved in 73% of these infections (Rochet et al., 2020). Moreover, Ismail et al. (2020) have described a large epidemic of skin abscesses among gold mine employers in South Africa. S. aureus PVL was responsible for this epidemic, due to cross-contamination resulting from poor hygiene practices. Invasive infections caused by Invasive infections caused by Invasive infections caused by Invasive infections caused by S. aureusS. aureusS. aureusS. aureus S. aureus is responsible for pneumonia which can have a serious prognosis, especially those corresponding to a nosocomial infection (nosocomial pneumonia) (Grousd et al., 2019). In a recent study in healthcare workers, colonization of saliva by S. aureus was the main cause of pneumonia and the oral environment acts as a potential reservoir for lower respiratory tract infection and development of pneumonia (Chiang et al., 2020). Another pathology caused by S. aureus is meningitis, a retrospective study has shown that when caused by S. aureus, meningitis has devastating clinical consequences and high mortality rates (36%) due to limited treatment options (Aguilar et al., 2010). Other more serious diseases are osteomyelitis and endocarditis. It was reported that during osteomyelitis, S. aureus presented 60.5% of positive cases in culture (Weiss et al., 2020). In addition, another study has confirmed the high prevalence of staphylococcal osteomyelitis with 85.1% of cases (Silago et al., 2020). According to Urish and Cassat (2020), treatment of osteomyelitis has remained largely unchanged over the past decades and focuses on personalized antibiotic therapy with correction of medical co-morbidities (Urish and Cassat, 2020). Thus, the majority of cases of osteomyelitis have been associated with large, deep purulent collections requiring surgical debridement (Kok et al., 2018), which increasingly complicates the patients care. Furthermore, S. aureus is the main causative agent of infectious endocarditis associated with high death rates and embolic events (Selton-Suty et al., 2012). This infection has been noted to be fatal in 20% to 65% of cases, and surviving patients suffer permanent sequelae from local invasion of cardiac structures (Murray, 2005). In addition to organic damage, the ubiquitous nature of S. aureus increases the risk of its passage into the blood from different primary foci by causing sepsis with distinct origins, namely cutaneous, urinary, dental and others. Indeed, MRSA sepsis was first reported as the underlying etiology of acute esophageal necrosis (Bawazir and Mustafa, 2020). In all described pathologies in the present work, one infection could be the complication of the other which is a pathological behavior frequently observed in S. aureus. In this sense, Al- bayati et al. (2020) have reported that S. aureus skin and soft tissue infections cause an unusual complication Zeouk I (2023). Not Sci Biol 15(1):11402 5 of persistent bacteremia which itself leads to complicated endocarditis in addition to an affinity of the involved strain for vertebral osteomyelitis (Al-bayati et al., 2020). Several studies have documented the risk of endocarditis as a complication of bacteremia and have confirmed that it is a serious complication (Bouchiat et al., 2015; Andersen et al., 2020). Furthermore, Grillo et al. (2020) have shown that the bacteremia itself can develop from urinary tract infections due to probing and catheterization, which leads to significant mortality considering that in many cases, the strains of MRSA were the most identified. Therefore, it is necessary to ensure the complete eradication of S. aureus infections and especially those of the skin. Indeed, the ability of all these infections to be life-threatening or not depends on several factors, in particular the virulent nature of the strain in question, the host's immune response and the intensity of resistance to the clinical protocol. Several studies have confirmed that the rate of infections worldwide gradually increases with increasing drug resistance and that clinical anti-infective treatment of resistant strains has become more difficult, especially with an immune response modulated by the bacterium (Guo et al., 2020; Scudiero et al., 2020). AntiAntiAntiAnti----biotherapy and emergence of resistance biotherapy and emergence of resistance biotherapy and emergence of resistance biotherapy and emergence of resistance Beta-lactams, aminoglycosides, and macrolides are among the main antibiotic families used in the treatment of S. aureus infections (Taylor, 2013). However, S. aureus has a remarkable ability to acquire resistance to different antibiotics with first the appearance of resistance to penicillin which has been so prevalent that the antibiotic is no longer effective, more than 90% of the strains are resistant (Lowy, 2003). This resistance has increased because, under massive and selective use of the antibiotic, certain strains of S. aureus express penicillinases able to hydrolyze the active beta-lactam site of the drug (Khoshnood et al., 2019). To this end, scientists have developed a new semi-synthetic penicillin able to resist against hydrolysis of staphylococcal beta-lactamases, methicillin (Pottinger, 2013). However, S. aureus has quickly developed several resistant strains (MRSA) characterized by a modified penicillin binding protein (PBP2a/c) and which loses its affinity for most antibiotics belonging to the beta-lactam family (Gajdács, 2019). This broad-spectrum resistance is mainly due to the mecA and mecC genes, located on staphylococcal chromosomal cassette mec (SCCmec) (Paterson et al., 2014). Although MRSA is the major pathogen identified in nosocomial pathologies, it is the most isolated germ also during community infections. This spread lead Moran et al. (2006) to suggest that among all S. aureus infections, a main proportion is caused by MRSA (Moran et al., 2006b). This suggestion has been widely confirmed in most of the skin, internal and visceral infections previously described. For example, in a study of military personnel with skin and soft tissue infections, 70% of the strains were resistant to methicillin (Landrum et al., 2012). Therefore, alternative anti-MRSA treatment recommendations were developed namely vancomycin which has become the mainstay of antibiotic therapy for many forms of MRSA infections (Diaz et al., 2017). Its activity is due to its binding to cell wall precursors, not to PBP2 (Pottinger, 2013). However, a phenomenon of gradual increase in MICs (minimum inhibitory concentrations) has been reported in many S. aureus isolates leading to the emergence of VISA (Vancomycin intermediate-resistant S. aureus), VRSA (Vancomycin - resistant S. aureus) and hetero-VRSA (Ahmad et al., 2018). Because of the rapid emergence of resistance in S. aureus strains and the spread of invasive MRSA infections, other antibiotics have been used. In a recent review, Guo et al. (2020) have documented the anti- MRSA antibiotic therapy and have reported that daptomycin is effective in the treatment of skin infections and bacteremia caused by MRSA. Unfortunately, the use of this antibiotic is limited in pneumonia because its mechanism of action is based on the destruction of the electrical potential of the plasma membrane without inhibiting the lipoteichoic acid, thus in the respiratory system, its activity is blocked by the alveolar surfactant Zeouk I (2023). Not Sci Biol 15(1):11402 6 (Taylor and Palmer, 2016). Moreover, Roch et al. (2017) have described a clinical case with MRSA infection in which the strain isolated was resistant to daptomycin (Roch et al., 2017). Indeed, MRSA have not developed resistance only to daptomycin but also to tetracycline and ciprofloxacin (Lai et al., 2017). Recently, Yamashita et al. (2019) have conducted a comparative study between daptomycin, vancomycin and azithromycin using a mouse model of MRSA pneumonia. They have demonstrated that treatment with azithromycin after 24 h of infection was effective, showing significantly longer survival and a low bacterial load in the lungs. Therefore, they suggested that this antibiotic may be a potential prophylactic agent for MRSA pneumonia (Yamashita et al., 2019). Despite intensified efforts to find an effective treatment, MRSA is still a major cause of mortality and morbidity around the world. In addition, the concomitant emergence of resistance is to be expected. According to Vestergaard et al. (2019), multidrug resistance of MRSA has considerably complicated the difficulties of scientific research (Vestergaard et al., 2019b). Virulence factorsVirulence factorsVirulence factorsVirulence factors The pathogenicity of S. aureus depends on many virulence factors in addition to the immune defenses of the host. These factors mainly include exoproteins such as secreted toxins (exotoxins) which disrupt host cells and interfere with immune responses, and surface proteins which play various roles in pathogenesis such as adhesion, but which is not a direct cause of toxicity towards host tissues (Vincenot et al., 2008). Expression of virulence factors by to Expression of virulence factors by to Expression of virulence factors by to Expression of virulence factors by to S. aureusS. aureusS. aureusS. aureus The pathophysiology of S. aureus infections begins with the colonization of surfaces producing different kinds of adhesion molecules, adhesins. Among the most important molecules is protein A which is a key factor in infections establishment (Palmqvist et al., 2002). Depending on the state of the host cell, protein A can act either by disguising S. aureus from the host's immune system by allowing it to resist against phagocytosis, or by completely deactivating the humoral immune response, or by inducing inflammatory cytokines and chemokines (Falugi et al., 2013; Gonzalez et al., 2019). In addition to protein A, some strains can form a microcapsule or develop a viscous polysaccharide substance called slime (Baselga et al., 1993). After attachment to the tissues of the host cell, S. aureus secretes several enzymes involved in different mechanisms such as the degradation of the host tissues, which promotes the extension of the infectious focus. The main extracellular enzymes include, among others, proteases, catalases, deoxyribonucleases, lipases, phosphatases, hyaluronidases and coagulases ... For example, Lehman et al. (2019) have shown that during the proliferation of skin abscesses, staphylococcal proteases played an important role in the digestion of peptides and amino acids necessary for the nutrient metabolism of S. aureus. In addition, the overexpression of these proteases was involved in the elevated pathogenesis of Fak (Fatty acid kinase) during skin infection (Ridder et al., 2020), while Treffon et al. (2020) have concluded that the two superoxide dismutases (SodA and SodM)- typical of S. aureus- compensates the survival of this bacterium during the destruction of leukocytes, which confirms that the interaction between these two enzymes is at the origin of the virulence and the persistence of S. aureus in the respiratory tracts and during cystic fibrosis, in addition to triggering inflammatory reactions and the fight against oxidative stress (Treffon et al., 2020). Other enzymes allow S. aureus to fight oxidative reactions, such as catalase which converts hydrogen peroxide into water and oxygen (Mandell, 1975). At the same time, S. aureus produces around forty exotoxins that make up about 10% of the total secretome, many of which have same functions due to remarkable structural similarity. According to their functions, several studies have shown that exotoxins fall into three main groups namely cytotoxins which act on the membranes of host cells leading to cell lysis and inflammation, Zeouk I (2023). Not Sci Biol 15(1):11402 7 toxic enzymes which damage host cells, and superantigens involved in the massive production of cytokines inducing proliferation of T and B cells (Tam and Torres, 2018). Major toxins include hemolysins, leukocidins, exfoliatins, enterotoxins, and toxic shock toxin. The toxin known as Panton-Valentine leukocidin (PVL) is known worldwide for its potential role in virulence and for its involvement in invasive infections. Thus, although only 5% of S. aureus strains produce PVL, it was widely studied. Indeed, PVL only causes cytotoxic changes in human monocytes and rabbits, because the cytotoxic activity towards these cells is highly specific and targets receptors coupled to human G proteins and those of rabbits (Spaan et al., 2015), therefore, these models are a good approach to better understand the complexity and pathology mediated by PVL. In this context, several studies have developed animal models on rabbits and have shown that individuals infected with wild-type PVL+ strains have developed more severe infections and higher mortality rates compared to individuals infected with PVL- strains (Diep et al., 2010; Lipinska et al., 2011). Moreover, to assess the production of PVL during human infections, Nakaminami et al. (2020) have conducted a recent study in which they have demonstrated that PVL-producing strains are widely distributed in skin infections and that the severity of these infections in patients infected with PVL+ is greater than that in patients infected with PVL- (Nakaminami et al., 2020). This severe progression of infections caused by PVL- producing strains has been confirmed in the literature (Petraitiene et al., 2020). Currently, Duployez et al. (2020) have reported a fatal case of a young adult with Covid-19, where the complication of viral infection was related to necrotizing pneumonia caused by S. aureus producing PVL (Duployez et al., 2020). Thus, the pathogenesis of S. aureus involves a multitude of virulence factors that do not occur at the same time, but their production is finely coordinated, which explains the increased pathogenicity of S. aureus and the variation in its clinical profile. According to Jenul and Horswill (2019), the regulation of virulent factors by S. aureus is subject to a complex network that integrates the host and signals derived from the environment (Jenul and Horswill, 2019). One of the most studied regulatory systems is the agr gene which is a "quorum sensing system" and which allows S. aureus to discover the density of its own population and to translate this information into a specific gene expression model in order to control the expression of its genes (Butrico and Cassat, 2020). Interaction hostInteraction hostInteraction hostInteraction host---- S. aureusS. aureusS. aureusS. aureus In S. aureus infection, the pathogen is recognized by cells in the infected tissue. Many cells can fulfill this role, macrophages, monocytes and neutrophils are major players in the control of staphylococcal infections (Accarias, 2014). Indeed, the composition of the wall of S. aureus itself is also involved in the recognition and initiation of the host's immune defense. Among these components, lipoproteins, lipoteichoic acid (LTA) and peptidoglycan (PGN) are the predominant (Leemans et al., 2003). Several studies have documented the interaction between S. aureus wall components and the host's immune response. The synergy between LTA and PGN leads to the production of a cascade of cytokines and chemokines allowing the recruitment of inflammatory cells in the host. Protein A with LTA can also stimulate the release of these inflammatory mediators(Gómez et al., 2004; Wu et al., 2020). Nevertheless, S. aureus can limit phagocytosis and to attenuate the pro-inflammatory responses of the host, which favors its persistence in the microenvironment, especially by modulating macrophages, or even inducing necroptosis in these cells by the previously described virulence factors (Patou et al., 2008). Therefore, S. aureus will be able to survive and disseminate in phagocytes (Horn et al., 2017). These interactions when regulated and the secreted cytokines are adjusted to balance between pro and anti-inflammatory ones, host cells successfully phagocytose and destroy the bacteria. However, S. aureus like any other infectious agent can also trigger an exaggerated immune response, during infection, if for example Zeouk I (2023). Not Sci Biol 15(1):11402 8 two cytokines are secreted in a high amount, they can participate in a fatal outcome (vom Berg et al., 2013). Indeed, it has been shown that PVL seems to have a major impact in the amplification of the immune responses of the host, Huang et al. (2020) have shown in a pneumonia model that S. aureus PVL- was responsible for the severity of the disease by increasing the expression of pro-inflammatory cytokines (Huang et al., 2020). In addition to the increased production of cytokines, PVL was able to modulate the host's immune response by decreasing the expression of TFNα (Yoong and Pier, 2012). In addition to immune responses, the metabolic pathway plays an important role in the interactions between S. aureus and the host. Lopez et al. (2017) have found that using the Fak enzyme complex, S. aureus is able to detect specific cis-unsaturated fatty acids which are very abundant in host tissue and which S. aureus is unable to produce (Lopez et al., 2017). In the same context, Potter et al. (2020) have conducted a comprehensive analysis of the metabolic needs of S. aureus during osteomyelitis, and they showed that the biosynthesis of aspartate represents a key metabolic node for the survival of staphylococci during infection, this biosynthesis has been greatly favored by the host's nutrient medium (Potter et al., 2020). Furthermore, Delekta et al. (2018) have shown that during infection, human lipoprotein particles provide a viable source of exogenous fatty acids for S. aureus (Delekta et al., 2018). Another study conducted by Lehman et al. (2019) has shown that during abscesses, collagen abundant at the site of infection in the host can serve as a nutrient reservoir for S. aureus overgrowth (Lehman et al., 2019). AntiAntiAntiAnti----S. aureusS. aureusS. aureusS. aureus plant extracts and isolated active compoundsplant extracts and isolated active compoundsplant extracts and isolated active compoundsplant extracts and isolated active compounds Plant extracts are an important source for the identification of active compounds against S. aureus (Table 1). The chemical diversity of these compounds is quite remarkable. Chabán et al. (2019) have conducted a bioguided fractionation of the extract prepared from the aerial part of Lepechinia meyenii, a species of the Lamiaceae family, selected from an ethnobotanical study. The ethanolic extract has been shown to be the most effective with MICs ranging from 62.5 to 500 μg/mL against strains of S. aureus resistant and sensitive to methicillin. Chemical fractionation resulted in the identification of carnosol, rosmanol and carnosic acid as active compounds with MICs ranging from 7.8 to 62.5 μg/mL against 15 strains of MRSA and 11 strains of MSSA (Chabán et al., 2019). Zheng et al. (2019) were interested in the study of different parts of the Garcinia esculenta species belonging to the Clusiaceae family and they have identified a new xanthone, (±) garciesculenxanthone C with bacteriostatic effect against MRSA, MSSA and VISA (Zheng et al., 2019). Table 1. Table 1. Table 1. Table 1. Some effective crude extract fractionated against S. aureus PlantsPlantsPlantsPlants FamillyFamillyFamillyFamilly ExtractExtractExtractExtract Phytochemical Phytochemical Phytochemical Phytochemical families of isolated families of isolated families of isolated families of isolated compoundscompoundscompoundscompounds ReferencesReferencesReferencesReferences Lepechinia meyenii (Walp.) (Arial part) Lamiaceae Ethanolic Diterpenes phenols and polyphenols (Chabán et al., 2019) Garcinia esculenta (Leave and twigs) Clusiaceae Ethanolic Xanthones, biphenyles (Zheng et al., 2019) Syzygium antisepticum (Leave) Myrtaceae Acetone/methanol/ water Sesquiterpenes (Yuan and Yuk, 2018) Pterocarpus erinaceus (Peel and root) Fabaceae Methanol/ Dichloromethane Triterpenoides and steroides (Tittikpina et al., 2018) Acacia polyacantha (Leave, peel and root) Fabaceae Methanolic Sterols, triterpenes, saponines, and flavonoïds (Ashu et al., 2020) Zeouk I (2023). Not Sci Biol 15(1):11402 9 Sesquiterpenes have also shown significant activity against S. aureus. Yuan and Yuk (2018) have characterized β-caryophyllene as the main compound in the active extract of Syzygium antisepticum. This sesquiterpene has induced damage to S. aureus membrane (Yuan and Yuk, 2018). In the same year, Tittikpina et al. (2018) have characterized active compounds in the extract of Pterocarpus erinaceus of the Fabaceae family. These compounds were identified as friedeline, 2,3 dihydroxypropyloctacosanoate, and β-sitosteryl-β-D- glucopyranoside, and they have showed interesting activity against MRSA with a MIC of 4 µg/mL (Tittikpina et al., 2018). Several studies have confirmed the richness of Fabaceae in species with antistaphylococcal activity (Ashu et al., 2020; Guidi et al., 2020). Recently, the bioguided fractionation of Boswellia dalzielii has confirmed the effectiveness of this process in the purification of compounds active against S. aureus. The crude extract has exhibited moderate activity (MIC = 250 µg/mL), the fractions have exhibited good activity with MICs ranging from 7.8 to 125 µg/mL, while the purified compounds from these fractions have exhibited promising activity with a MIC value of 3.125 µg/mL (Tegasne et al., 2020). Further studies have considered bioguided fractionation for the discovery of compounds able to inhibit biofilm formation by S. aureus. In this context, Manilal et al. (2020) have reported the antistaphylococcal activity of Moringa stenopetala selected among three other species. Its ethanolic extract has shown a bacteriostatic effect against MRSA by inhibiting its growth in the preformed matrix of the biofilm. Chemical analysis of this extract revealed 12 active compounds belonging to different chemical classes (Manilal et al., 2020b). Moreover, biofilm formation by S. aureus has been shown to be highly influenced by Frangula alnus extract rich in flavonoids and anthraquinones such as catechin and emodin (Đukanović et al., 2020). Recently, our team has conducted a bioguided fractionation of the ethanolic extract of Rhamnus alaternus, the purification procedure allowed us to identify the same families anthraquinone and flavonoids, emodin being the most active compound without cytotoxicity towards murine macrophages (Zeouk et al., 2021). ConclusionsConclusionsConclusionsConclusions S. aureus represents a causative agent of different serios diseases that constitutes an increasing health problem. Current antibiotics are not satisfactory despite the advances in science. The multiplicity of diseases caused by S. aureus is mainly related to the strains as well as the immune response of the infected host. Thus, the development of new antibiotics with a noticeable effect and reduced toxicity remains an urgent need especially from natural antimicrobial agents, which could constitute a promising therapeutic approach. Poincianella pluviosa (Peel) Fabaceae Ethanolic Polyphenols (Guidi et al., 2020) Boswellia dalzielii (Peel) Burceraceae Methanolic Terpenoides and triterpenes (Tegasne et al., 2020) Moringa stenopetala (Leave) Moringinaceae Ethanolic Several families (Manilal et al., 2020a) Frangula alnus (Peel) Rhamnaceae Ethyl acetate Phenols, flavonoids and anthraquinones (Đukanović et al., 2020) Rhamnus alaternus (Leave) Rhamnaceae Ethanolic Anthraquinones Flavonoids (Zeouk et al., 2021) Zeouk I (2023). Not Sci Biol 15(1):11402 10 Authors’ ContributionsAuthors’ ContributionsAuthors’ ContributionsAuthors’ Contributions The author read and approved the final manuscript. Ethical approvalEthical approvalEthical approvalEthical approval (for researches involving animals or humans) Not applicable. AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements This research received no specific grant from any funding agency in the public, commercial, or not-for- profit sectors. Conflict of InterestsConflict of InterestsConflict of InterestsConflict of Interests The authors declare that there are no conflicts of interest related to this article. ReferencesReferencesReferencesReferences Accarias S (2014). Impact du phénotype des macrophages résidents sur la nature de la réponse inflammatoire précoce lors d’une infection par Staphylococcus aureus. Aguilar J, Urday-Cornejo V, Donabedian S, Perri M, Tibbetts R, Zervos M (2010). Staphylococcus aureus meningitis case series and literature review. Medicine (Baltimore) 89:117-125. https://doi.org/10.1097/MD.0b013e3181d5453d Ahmad S, Raqeeb A, Ali F, Hameed MS, Anwar M (2018). 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