https://orcid.org/0000-0002-5469-8120
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Abstract
Aim: To evaluate the action of promethazine, fluoxetine and carbonyl cyanide 3-chlorophenylhydrazone as efflux pump inhibitors (EPIs) against multidrug-resistant Pseudomonas aeruginosa. Methods: The effect of the compounds was evaluated in planktonic cells and bacterial biofilms. Accumulation tests were performed with ethidium bromide to prove their action as EPIs. Then, they were associated with antimicrobials. Results: Effect on planktonic cells and biofilms was found. Assays with ethidium bromide indicate their action as EPIs. Significant reductions in the metabolic activity of biofilms were observed after the association with the antimicrobials, especially for meropenem. Conclusion: It is possible to prove the action of these compounds as EPIs for P. aeruginosa and demonstrate the relevance of efflux pumps in antimicrobial resistance.
Overexpression of efflux pumps is an important route of antimicrobial resistance for Pseudomonas aeruginosa.
Efflux pump inhibition has been a proposed mechanism to regain the efficacy of antimicrobials that are extruded by these efflux systems, so many researchers have been studying new efflux pump inhibitors (EPIs).
This study aimed to evaluate the action of promethazine (PMZ), fluoxetine (FLU) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) as EPIs against multidrug-resistant P. aeruginosa.
PMZ, FLU and CCCP show antimicrobial effects against multidrug-resistant P. aeruginosa, although the concentrations are higher than those that can be achieved in a patient infected with this pathogen.
PMZ, FLU and CCCP eliminated the metabolic activity and reduced the biomass of mature P. aeruginosa biofilms.
Subinhibitory concentrations of PMZ, FLU and CCCP increased the fluorescence of ethidium bromide-treated cells when compared with the untreated groups, indicating the action of these compounds as EPIs.
Bacterial cells were not sensitized to the antimicrobials after association with the EPIs, but important reductions in the MICs of the antimicrobials were observed, indicating that efflux pumps are one of the mechanisms contributing to the high MICs of multidrug-resistant strains.
PMZ, FLU and CCCP reduced the minimal eliminatory concentrations of the antimicrobials after association, indicating that efflux pumps may play an important role in maintaining P. aeruginosa biofilms.
Author contributions
VC Pereira, AS Freitas, PRH Souza, ALC Parra, RFM Guedes, and JA Brasil carried out the experimental assays and manuscript drafting. GMM Guedes, PCP Sousa, RA Cordeiro, MFG Rocha, and JJC Sidrim supervised, performed formal analyses and revised the manuscript. DSCM Castelo-Branco conceptualized and supervised the research and performed the final drafting.
Financial disclosure
This work was supported by grant from the National Council for Scientific and Technological Development (CNPq; Brazil, process nos. 405312/2021-0 and 310826/2020-9), the coordination for the Improvement of Higher Education Personnel (CAPES; Brazil) and the Cearense Foundation for Scientific and Technological Development Support (FUNCAP; Brazil). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.