# Anthraquinone Rhein Exhibits Antibacterialativity against _Staphylococcus aureus_
## 1 Introduction  
Staphylococcus aureus (S. aureus) represents an important opportunistic pathogen, able of adapting rapidly to adverse environmental conditions and evading the immune system [1, 2]. It causes a wide range of clinical manifestations, ranging from skin and soft tissue infections to systemic and toxin-mediated affections with high prevalence [3, 4]. _S. aureus_ infection abides a major and prevalent reason of morbidity and mortality in hospitalized patients, despite the antibiotic treatment and prevention of infectious diseases [5]. Each year in Europe, approximately 25,000 hospitalized patients die from a severe resistant bacterial infection, and a substantial part of them is due to _S. aureus_[6]. This strain causes blood infections with an incidence of 20-50 cases per 100,000 inhabitants per year, with mortality levels of around 10-30% [7]. Methicillin-resistant _S. aureus_ (MRSA)has been recognized as a global priority pathogen by the World Health Organization, causing growing concern around the world [8; 9]. Conventional antibiotics are no longer suitable against most MRSA due to the rapid development of antibiotic resistance [10]. Glycopeptides and latest-generation antibiotics, such as linezolid, daptomycin and the newly available fifth-generation cephalosporins, still show high efficiency against resistant _S. aureus_, although the development of strains resistant to these antibiotics is clearly on the rise [11]. The prevalence of Vancomycin-resistant _S. aureus_ was 2% before 2006, 5% in 2006-2014 and 7% in 2015-2020, showing a 3.5-fold increase between 2006 and 2020 [12]. Moreover, surveillance studies reported a global resistance rate of _S. aureus_ to Daptomycin and Linezolid of 0.3% [13; 14]. The emergence of resistant strains is often faster than the development of new antibiotics. Moreover, the number of Food and Drug Administration approved antibiotics has been reduced in the last three decades, limiting the treatment possibilities of resistant bacteria [11; 15]. Therefore, antibacterial agents with new modes of action and alternative pharmacological targets are urgently needed. Natural products are an important source of novel antimicrobial agents, and their use is associated with the following advantages: (i) low cytotoxicity; (ii) reduced propensity to develop resistance; (iii) high chemical diversity; and iv) material of abundant and cheap origin [16; 17]. In recent years, many plant-derived compounds have been studied for their antibacterial potential against _S. aureus_ strains. [PERSON] et al. reported the antibacterial potential of (Z, Z)-5-(trideca-4,7-dienyl) resercinol against _S. aureus_ strains with MIC values of 8 \(\upmu\)g/mL [18]. [PERSON] et al. demonstrated that Sanguinarine possesses strong antibacterial activity against _S. aureus_, recording MIC values of 6.25 \(\upmu\)g/mL [19]. Additionally, [PERSON] et al. proved the antibacterial effect of Berberine against MRSA with MIC values of 128 \(\upmu\)g/mL [20]. Rhein is an anthraquinone, constituent of several medicinal plants, such as _Rheum pulnutum L., Cassia tora L., Polygonum multiform Thumb._ and _Aloe barbadensis Miller_ (Figure 1) [21]. Numerous evidence reports the hepatocyte, neuroprotective, antioxidant, antitumor, antidiabetic and anti-inflammatory role of this natural product [22]. Furthermore, Rhein's antibacterial potential has been proven against different Gram-positive and Gram-negative pathogens, such as _Streptococcus mutans, Propriibacterium acnes, Pseudomonas aeruginosa_, etc. [23; 24; 25; 26]. The present study aims to evaluate the antibacterial potential of Rhein against standard and clinical isolated _S. aureus_ strains in the planktonic and biofilm state.