Antimicrobial resistance (AMR) has emerged in Staphylococcus aureus stepwise. The introduction of penicillins such as penicillin G in the 1940s led to penicillinase-based resistance due to the blaZ and related genes. blaZ encodes penicillinase. Upon the introduction of penicillins that are resistant to penicillinases -such as methicillin and oxacillin -methicillin-susceptible strains (MSSA) gave way to MRSA when the bacterium acquired mecA. MRSA express both, penicillin-binding protein 2a (PBP2a) as well as penicillinases. MRSA are, consequently, resistant to most β-lactams. Vancomycinonce considered a "drug of last resort" -became the frontline therapy against MRSA, giving rise to vancomycin-intermediate resistant (VISA) strains. VISA isolates are often also resistant to β-lactams, making antimicrobials such as oxazolidinones (e.g., linezolid), and streptogramins (e.g., quinupristin-dalfopristin) frontline treatments. As can be expected, resistant cases are emerging against these and other treatment options. Resistance will only increase with antimicrobial use. Community-and hospital-acquired S. aureus infections are common today. Community-acquired MRSA infections are widespread now due to a variety of reasons, including the current opioid crisis and the shared use of dirty needles. For instance, in North Carolina alone, the number of infective endocarditis cases increased 20-fold across a 5-year span, with a concomitant increase in financial burden for society. Since S. aureus is a major etiological agent in infective endocarditis, a large part of this burden can be attributed directly to antimicrobial resistance in this pathogen. We need novel ways of fighting S. aureus infections.