Semicarbazone and thiosemicarbazone derivatives associated with antibiotics inhibit β-lactamases and efflux pumps in Staphylococcus aureus strains

The production of the β-lactamase enzyme and the presence of efflux pumps in Staphylococcus aureus represent crucial mechanisms in antibiotic resistance. This microorganism constitutes a serious public health problem, triggering hospital-acquired infections and, in extreme cases, resulting in the death of the host. Thus, the development of an effective medication against multidrug-resistant bacteria becomes imperative, minimizing side effects. In this study, six semicarbazone and thiosemicarbazone derivatives (3a, 3b, 3c, 3d, 3e and 3f) were evaluated against the strains K4414, K4100, and K2068, which have QacA/B, QacC, and MepA efflux systems, respectively, with K4414 and K4100 producing β-lactamases. Direct antibacterial activity and β-lactamase inhibition were analyzed using the broth microdilution method, determining the minimum inhibitory concentration (MIC). The ability to inhibit efflux pumps was assessed using the MIC of substances at sub-inhibitory concentrations, in combination with the antibiotics ampicillin, oxacillin, ciprofloxacin, and the DNA intercalating dye, ethidium bromide. Although all compounds showed MIC values > 1024 μg/mL, considered inactive, in combination with antibiotics, a significantly enhancing activity of MIC was observed, especially for the compounds 3d and 3e. These results indicate that 3d and 3e have the potential to act as antibiotic enhancers. Subsequent studies can be conducted to elucidate their specific mechanisms of action, paving the way for considering these compounds as valuable alternatives in the pharmaceutical industry.