Compared to glycopeptides and linezolid, beta-lactams are superior anti-staphylococcal agents. Generally considered safe, beta-lactams are the #1 option for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. This advantage disappears for methicillin-resistant Staphylococcus aureus (MRSA) infections. In these cases, doctors turn to other antibiotics whose increased toxicity, requirement of PICC line use, and weeks of hospitalization are severe drawbacks. Survival is determined by patient age, comorbidities, severity of the acute infection, timely treatment, and effective treatment. While the first two factors are beyond the control of pharmaceutical therapy, anti-staphylococcal penicillins can be used effectively against mild and severe MSSA infections without delay. Clinical infectious disease experts would prefer to use beta-lactams against MRSA, but this approach requires a way to disable resistance mechanisms. As described in this presentation, beta-lactam antibiotics that target cell-wall synthesis penicillin binding proteins (PBPs) are potentiated against MRSA in a formulation that retains potency in serum while having minimal cytotoxicity. Antimicrobial resistance due to PBP2a and PBP4 requires wall teichoic acid (WTA) as an essential co-factor for proper location and orientation. Instead of targeting the PBP2a directly, we have created a library of cationic polymer potentiators that target WTA to prevent PBP2a and PBP4 from functioning properly; restoring susceptibility of MRSA to beta-lactams. We demonstrate anti-MRSA efficacy for numerous penicillins, carbapenems, and cephalosporins. Data demonstrate the mechanism of action and the mode of action. We report in vivo maximum tolerable dose (MTD or LD0) of compounds in the potentiator library. Our approach allows treatment of MSSA, MRSA, and other drug-resistant bacteria using prescription antibiotics without the need for hospitalization. Likewise, our approach allows timely and effective treatment before the infection progresses to cause significant patient morbidity.

Potentiating pencillins, carbapenems, and cephalosporins to kill MRSA

256th National Meeting (2018)

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