Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7-9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of beta-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants.

Automated summary

This study explores new derivatives that can improve the antibacterial activity of conventional antibiotics and help overcome MRSA infections. The results show that the 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) is the most effective in enhancing the activity of oxacillin, even at low concentrations. In addition, thiazole derivatives have shown complex mode of action in S. aureus isolates, acting as both oxacillin and erythromycin conjugators, potentially affecting the Msr(A) efflux pump. These findings suggest that imidazolones have a high potential to become commercially available antibiotic adjuvants.