Here, we report the discovery of P2As as a novel class of chemical enhancers that re-sensitize MRSA to penicillin G by up to 64-fold by suppression of β-lactamase gene expression. The structure of the prototype P2A is shown in Fig 1 . These chemicals are relatively small (~350-400 Da) and hence have high potential for further optimization and development. Limited structural changes could be made to the core motif, suggesting P2As function at a specific binding pocket. Little to no activity was observed in altering the MIC of penicillin G against VISA, so the phenotype is specific to MRSA as well. All this suggests specific modulation of a single target, although further investigation is needed to establish this beyond doubt.