![]() While antimicrobial discovery is still the focus of our attempts at solving the resistance problem, nontraditional options are also being considered. Resistance will only increase with antimicrobial use. As can be expected, resistant cases (6) are emerging against these and other treatment options. (4) VISA isolates are often also resistant to β-lactams, (5) making antimicrobials such as oxazolidinones (e.g., linezolid) and streptogramins (e.g., quinupristin-dalfopristin) frontline treatments. Vancomycin─once considered a “drug of last resort”─became the frontline therapy against MRSA, (3) giving rise to vancomycin-intermediate resistant (VISA) strains. (1,2) MRSA is, consequently, resistant to most β-lactams. MRSA expresses both penicillin-binding protein 2a (PBP2a) as well as penicillinases. 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. Staphylococcal penicillinase is secreted outside the cell and destroys sensitive β-lactams before they can act upon the pathogen. (1) The introduction of penicillins such as penicillin G in the 1940s led to penicillinase-based resistance via blaZ and related genes. P2As are a practical implementation of Moreillon’s principle of suppressing β-lactamase activity to make penicillin G useful against MRSA, without employing direct enzyme inhibitors.Īntimicrobial resistance (AMR) has emerged in Staphylococcus aureus stepwise. P2As modulate an unknown global regulator but not established antimicrobial-enhancement targets Stk1 and VraS. Oxacillin was not enhanced due to PBP2a expression, demonstrating the advantage of penicillin G over penicillinase-insensitive β-lactams. ![]() Here, we show that 50 μM pyrimidine-2-amines (P2As) reduce the minimum inhibitory concentration (MIC) of penicillin G against MRSA strains by up to 16-fold by reducing β-lactamase activity but not by direct inhibition of the enzyme. Additionally, animals treated with a combination of direct β-lactamase inhibitors like sulbactam and clavulanate with penicillin G developed resistant infections, clearly demonstrating that direct inhibition of β-lactamase is not a good strategy. Penicillin G overcame PBP2a because β-lactamase activity was blocked. Yet, Moreillon and others have demonstrated that penicillin G is as potent against a β-lactamase gene knockout strain, as vancomycin is against wild-type MRSA. Most research on antimicrobial enhancement against MRSA focuses on oxacillin due to β-lactamase expression. Enhancing β-lactams against MRSA would revive its clinical utility. Antimicrobial discovery is difficult, and resistance exists against most treatment options. Β-Lactamase (penicillinase) renders early, natural β-lactams like penicillin G useless against methicillin-resistant Staphylococcus aureus (MRSA), which also expresses PBP2a, responsible for resistance to semisynthetic, penicillinase-insensitive β-lactams like oxacillin. ![]()
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