Abstract
Drug efflux pumps are one of the major elements used by antibiotic-resistant bacteria. Efflux pump inhibitors (EPIs) are potential therapeutic agents for adjunctive therapy, which can restore the activity of antibiotics that are no longer effective against pathogens. This study evaluated the seaweed compound diphenylmethane (DPM) for its EPI activity. The IC50 and modulation results showed that DPM has no antibacterial activity but can potentiate the activity of antibiotics against drug-resistant E. coli. Time-kill studies reported that a combination of DPM and erythromycin exhibited greater inhibitory activity against drug-resistant Escherichia coli. Dye accumulation and dye efflux studies using Hoechst 33342 and ethidium bromide showed that the addition of DPM significantly increased dye accumulation and reduced dye efflux in drug-resistant E. coli, suggesting its interference with dye translocation by an efflux pump. Using MALDI-TOF, it was observed that the addition of DPM could continuously reduce antibiotic efflux in drug-resistant E. coli. Additionally, DPM did not seem to damage the E. coli membranes, and the cell toxicity test showed that it features mild human-cell toxicity. In conclusion, these findings showed that DPM could serve as a potential EPI for drug-resistant E. coli.
Highlights
Drug resistance has significantly increased uncertainty over treatment and medical costs, as well as the mortality rate from bacterial infections
The antibiotics clarithromycin, erythromycin, and ciprofloxacin have been reported as substrates of the E. coli efflux pump AcrB [31,32], and the construct E. coli Kam3 harboring pSYC-acrB (Kam3-AcrB) was used in the modulation assays
The data from this study indicated that DPM could potentiate antibiotic activity for drug-resistant E. coli by reducing the efflux pump efficiency
Summary
Drug resistance has significantly increased uncertainty over treatment and medical costs, as well as the mortality rate from bacterial infections. The use of efflux pump inhibitors (EPI) has rapidly drawn attention as a promising approach to treat infections caused by pathogens expressing multidrug-resistant efflux pumps [10,11]. Their use in adjunctive therapy may enhance/restore the activities of existing antibiotics by interfering with efflux pumps; it may even allow therapeutically ineffective antibiotics to be re-introduced into clinical practice. Piperine could increase the bactericidal activity of rifampicin and significantly extend its post-antibiotic effect, by inhibiting drug efflux pump Rv1258c in Mycobacterium tuberculosis [21]. An organic compound, diphenylmethane (DPM), was identified in the extracts of Gracilaria sp., and its EPI activity was investigated
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