New chalcone analogues with potential bacterial efflux pump inhibitory effect

Chalcones comprise a class of natural products possessing two aromatic rings linked by an enone. These compounds show extensive biological activities, including antimicrobial activity in multidrug resistant bacteria.

Considering the potential of these compounds as antimicrobial agents, a library of chalcones and their analogues was synthesized, and the minimum inhibitory concentrations were determined by broth microdilution methods. Antibacterial activity was accessed for reference strains (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853). Multidrug-resistant isolates, ESBL E. coli SA/2, MRSA S. aureus 66/1 and VRE E. faecalis B3/101, were used for the synergy assay with antibiotics, cefotaxime, oxacillin and vancomycin, respectively. Most of the compounds displayed promising results in combination with antibacterial drugs, while not displaying relevant antimicrobial activity. Further insights into the mechanisms through which these compounds could exert synergistic activity were pursued, and their potential to inhibit bacterial efflux pumps was investigated in Gram positive (S. aureus MRSA 272123) and Gram negative (a mutant strain of Salmonella enterica Typhimurium expressing the AcrAB-TolC efflux system with the acrA gene inactivated) bacteria. The assay is based on the intracellular accumulation of the efflux pump substrate ethidium bromide measuring the increase in fluorescence in the presence of a potential efflux pump inhibitor. By this approach, some chalcone analogues displayed promising activity as bacterial efflux pump inhibitors.