Antibiotic resistance in the past 50 years has increasingly challenged treatment of bacterial infections. A compelling example is Staphylococcus aureus, which exhibited resistance to penicillin as early as the 1940s. This resistance was initially addressed in 1959, with the introduction of methicillin and other semi-synthetic second-generation penicillins. Only two years later, in 1961, a new variant of resistant S. aureus appeared, which became known as methicillin-resistant S. aureus (MRSA). MRSA strains today are essentially resistant to the entire class of β-lactam antibiotics. Only vancomycin, linezolid, ceftaroline, and daptomycin are left against S. aureus infections and resistant strains against these antibiotics have already been reported. Clostridium difficile, a Gram-positive spore-forming and toxin-producing bacteria, is another example of a bacterial pathogen facing the same destiny.I describe herein the discovery of two classes of antibiotic potentiators, the cinnamamide and cinnamonitrile families, and one antibacterial, the picolinamide family, to address this issue. The first two potentiate the activity of oxacillin (a penicillin member of the β-lactam class) such that susceptibility of S. aureus to oxacillin is restored. A total of 50 analogues of the cinnamamide family were prepared and screened. Seven of these compounds showed a dramatic potentiation of the antibacterial activity, lowering the minimum-inhibitory concentrations (MICs) for the antibiotic by as much as 64- to 128-fold. Of the 84 examples of the cinnamonitrile family, five compounds showed broad potentiation against six important strains of MRSA, one vancomycin-intermediate S. aureus (VISA) strain, and one linezolid-resistant S. aureus strain. One especially meritorious compound exhibited potentiation of >4,000-fold (reduction of MIC from 256 to 0.06 mg L–1) against a linezolid-resistant MRSA strain at 8 µM. The antibacterial class represented by the picolinamide family was evaluated against S. aureus and C. difficile. Out of the 111 derivatives prepared, one emerged for its positive pharmacological attributes, such as activity (MIC against C. difficile of 0.12 mg L–1), solubility, and low toxicity levels. This compound was tested on an in vivoC. difficile recurrent infection mouse models, showing better efficacy (survival) than vancomycin.