Treatment of Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) infections remain a significant challenge in healthcare, as its resistance against antibiotics makes it extremely difficult to treat. MRSA maintains resistance to beta-lactams through resistance factors such as penicillin binding protein 2a (PBP2a) and beta-lactamase. Combining direct beta-lactamase inhibitors like sulbactam with penicillin G fails to combat infections in animal models. This is not the case when beta-lactamase expression is inhibited (rather than directly inhibiting the enzyme) – now treatment with penicillin G works very well. Thus, chemicals that suppress beta-lactamase will help penicillin G regain effectiveness against MRSA. We are studying a class of chemicals known as pyrimidine-2-amines (P2As) that have reduced the minimum inhibitory concentration (MIC) of penicillin G by 8-fold in several MRSA strains, as well as the MIC of ampicillin and amoxicillin (other beta-lactamase-sensitive antibiotics) by 4-fold. We have shown that these chemicals function specifically to inhibit beta-lactamase expression, but not the enzyme itself. Further investigations into such chemicals will help bring penicillin G back into the clinic for treating MRSA infections.

Beta-lactamase suppression to treat methicillin-resistant Staphylococcus aureus infections

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