Spicing up urinary tract infections: synergistic action of fosfomycin with trans-cinnamaldehyde - insight to the mode of action
Abstract
Abstract Objectives Fosfomycin (FOS) remains an important therapeutic option for urinary tract infections caused by uropathogenic Escherichia coli (UPEC), but specific virulence traits as biofilm formation, metabolic adaptation, and antimicrobial resistance may limit its efficacy. This study investigated whether the natural compound, trans-cinnamaldehyde (t-CA) potentiates FOS activity against UPEC and explored the underlying mechanisms of its effect Methods The interaction between t-CA and FOS was assessed using checkerboard assays, time-kill analysis. We evaluated biofilm viability and structure using confocal and scanning microscopy as well as catheter-associated biofilm models. Next, effects on membrane integrity, cell-surface properties, membrane potential, intracellular pyruvate levels, and resistance evolution during serial passage were evaluated. Molecular docking was used to explore potential interactions of t-CA with enzymes involved in pyruvate metabolism. Galleria mellonella infection model was employed to evaluate in vivo therapeutical efficiency. Results t-CA potentiated FOS activity against laboratory, reference, and clinical UPEC strains, with synergistic or additive interactions observed across the tested collection. The combination enhanced bacterial killing, reduced biofilm viability and biomass, and disrupted biofilm architecture. In catheter-associated biofilms, combined treatment markedly impaired surface-associated UPEC communities. t-CA reduced…
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