From formulation to in vivo model: A comprehensive study of a synergistic relationship between vancomycin, carvacrol and cuminaldehyde against Enterococcus faecium
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Abstract
Vancomycin Resistant Enterococcus faecium (VRE) has become endemic in healthcare settings, reducing treatment options for enterococcal infections. New antimicrobials for VRE infections are a high priority, but the development of novel antibiotics is time-consuming and expensive. Essential Oils (EOs) synergistically enhance the activity of some existing antibiotics, suggesting that EO-antibiotic combinations could re-sensitise resistant bacteria and maintain the antibiotic repertoire. The mechanism of re-sensitisation of bacteria to antibiotics by EOs is relatively understudied. Here, the synergistic interactions between carvacrol (1.98 mM) and cuminaldehyde (4.20 mM) were shown to re-establish susceptibility to vancomycin (0.031 mg/L) in VRE, resulting in bactericidal activity (4.73 log10 CFU/mL reduction). Gene expression profiling, coupled with β-galactosidase leakage and salt tolerance assays suggested that cell envelope damage contributes to the synergistic bactericidal effect against VRE. The EO-vancomycin combination was also shown to kill clinical isolates of VRE (2.33-5.25 log10 CFU/mL reduction) and stable resistance did not appear to develop even after multiple passages. The in vivo efficacy of the EO-vancomycin combination was tested in a Galleria mellonella larvae assay; however no antimicrobial action was observed, indicating that further drug development is required for the EO-vancomycin combination to be clinically useful for treatment of VRE infections.