Pyrimidine-2-amines increase susceptibility of methicillin-resistant Staphylococcus aureus to penicillin G

β-lactamase (penicillinase) renders early β-lactams like penicillin G useless against methicillin-resistant Staphylococcus aureus (MRSA). Antimicrobial discovery is difficult, and resistance exists against most treatment options. Enhancing β-lactams against MRSA would revive their clinical utility. 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. Yet, direct β-lactamase inhibitors like sulbactam and clavulanate gave rise to penicillin G resistance. Instead, 50 μM pyrimidine-2-amines (P2A) reduce the minimum inhibitory concentration (MIC) of penicillin G against MRSA strains by up to 64-fold by reducing β-lactamase expression. PBP2a prevented oxacillin enhancement, demonstrating the advantage of penicillin G over penicillinase-insensitive β-lactams. P2As modulate an unknown global regulator, but not established antimicrobial-enhancement targets Stk1 and VraS. 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.