While antimicrobial discovery is still the focus of our attempts at solving the resistance problem, non-traditional options are also being considered. Identifying enhancers (chemicals that increase the potency of clinically relevant antimicrobials) has already resulted in approved, marketed drugs such as Augmentin™, a combination of amoxicillin with clavulanate; Clavulanate inhibits penicillinases, preventing the deactivation of amoxicillin, thus making it more effective against β-lactamase producing MSSA. These successes at devising enhancers are highly promising, even if Augmentin is not clinically useful against MRSA infections due to the expression of PBP2a, whose expression is widely expected to overcome β-lactams. On the other hand, Moreillon and others have put forward strong evidence that older, natural penicillins and aminopenicillins have ~10-fold more affinity for PBP2a than semi-synthetic penicillins such as oxacillin, if penicillinase is not present. They also found that these penicillins sterilize infective endocarditis vegetations in rabbits within 4 days of therapy if penicillinase was ineffective. Penicillin G was comparable to vancomycin in an animal model when penicillinase was not present; Penicillin G cured just as many rabbits infected with penicillinase-negative MRSA, as vancomycin did against wild-type MRSA. Penicillin G was actually more potent than vancomycin against the penicillinase negative MRSA strain (Log10CFU/gram of infected tissue: ~4.6±2 vs. ~7±1 after treatment respectively). This is critical because vancomycin is first-line therapy for MRSA infections. However, treatment of infected animals with a combination of high-dose sulbactam with penicillin G was associated with failures due to resistant strains. It is evident that irreversible penicillinase-based penicillin inactivation will reduce the amount of the antimicrobial available to act on its target, when agents like sulbactam or clavulanate are used. As a result, resistant mutants are able to survive. Notably, penicillinase knockout strains did not demonstrate similar failures or resistance. In light of the above, our hypothesis is that inhibiting β-lactamase expression will enhance the potency of penicillinase-sensitive penicillins against MRSA. This suggests that blaZ suppression is an alternative to direct penicillinase inhibitors like sulbactam and clavulanate. If successful, this adaptation of Moreillon's strategy could help revive the clinical utility of natural penicillins, which are currently considered of little to no clinical utility against this pathogen.