11 General Introduction 1 Concerning the pathogen, S. aureus is capable of colonizing healthy individuals as well as causing catastrophic disease in many different animal hosts, including humans. It produces various virulence and immune evasion factors, interfering with the immune system of the host and preventing it from effectively warding off recurrent infections [7]. S. aureus has unique features, such as the ability to cause metastatic infections throughout the human body, mainly facilitated by the expression of surface proteins that mediate adhesion, and the tendency to persist in the bloodstream despite appropriate antibiotics. Besides, the pathogen has the ability to form biofilms leading to chronic device infections [8], and to produce multiple exotoxins, some of which are accountable for toxic shock syndrome and food poisoning [9]. Environmental factors are of influence on the variability of S. aureus as well, such as the prevalence in the community and the timely initiation of effective treatment. A major additional complicating factor is the capacity of S. aureus to develop antimicrobial resistance. Antimicrobial resistance and Staphylococcus aureus Antimicrobial resistance has significantly increased over the past decades, and is now in the top ten public health threats facing humanity, as declared by the World Health Organization (WHO) [10]. As a natural evolutionary response to antimicrobial exposure, bacteria develop resistance to antibiotics through multiple different mechanisms [11]. For S. aureus, the most relevant resistance mechanism is by acquiring a mecA gene through horizontal transfer of a mobile genetic element designated staphylococcal cassette chromosome mec (SCCmec), leading to methicillin resistance. The mecA gene encodes for a specific penicillin binding protein (PBP2a), which crosslinks bacterial peptidoglycans and has low affinity for beta-lactam antibiotics, causing resistance to almost all antibiotics within this class [12]. Methicillin-resistant S. aureus (MRSA) was first described in the early 1960s, shortly after the introduction of the antibiotic methicillin [13]. However, modern molecular phylogenetics suggest that MRSA emerged already by natural selection in the pre-antibiotic era and was further selected for by the widespread use of penicillin since the 1940s. Methicillin only provided better selective pressure for the bacterium to spread [14, 15]. Responsible for over 100,000 deaths in 2019, MRSA is currently the leading cause of mortality attributable to antimicrobial resistance in the world [16]. As a major actor in the field of antimicrobial resistance, MRSA also serves as an indicator for antimicrobial resistance in the global sustainable development goals of the United Nations [17].
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