Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) are an important etiological agent in multiple serious infections. Beta-lactams are considered useless against them, with few exceptions. Resistance has emerged to virtually all alternative treatments. The oldest beta-lactams, such as penicillin G, were never a viable treatment because most Staphylococci had acquired the ability to express penicillinases long before MRSA emerged as pathogens. If we were to regain the clinical utility of penicillinase-susceptible beta-lactams (PSBLs) such as penicillin G, it would also help us conserve newer antimicrobials. In fact, it has been shown that PSBLs are 10-fold more potent than penicillinase-resistant beta-lactams (PRBLs) if penicillinases are inactivated. We have recently identified a series of chemicals (pyrimidin-2-diamines, P2As) that suppress beta-lactamase expression in USA300 MRSA strains, which are a common cause of infections. A preliminary structure-function relationship study tells us P2As are able to enhance the minimum inhibitory concentration (MIC) of the archetypal PSBL, penicillin G, between 4- and 64-fold, but not that of PRBLs. The best P2A is ~375 Da, and active at 50 micromolar, so the potential for development is quite high. P2As retained activity in stk1 and vraS gene knockouts, both of which are connected to enhancement of beta-lactam potency. Therefore, we hypothesize P2As act at a putative new target, which remains unknown at this time. Rationally optimizing P2As against this putative target will likely provide us with alternatives to beta-lactam/beta-lactamase inhibitor combinations used clinically.

Power to the penicillins: Enhancing the potency of penicillinase-sensitive beta-lactams against <i>Staphylococcus aureus</i>

ACS Spring 2022

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Power to the penicillins: Enhancing the potency of penicillinase-sensitive beta-lactams against Staphylococcus aureus