Inhibition of the NorA efflux pump of S. aureus by (Z)-5-(4-Fluorobenzylidene)-Imidazolidines

Martín S Faillace; Antonio L Alves Borges Leal; Felipe Araújo de Oliveira Alcântara; Josie H L Ferreira; José P de Siqueira-Júnior; Carlos E Sampaio Nogueira; Humberto M Barreto; Walter J Peláez

doi:10.1016/j.bmcl.2020.127670

Inhibition of the NorA efflux pump of S. aureus by (Z)-5-(4-Fluorobenzylidene)-Imidazolidines

Bioorg Med Chem Lett. 2021 Jan 1:31:127670. doi: 10.1016/j.bmcl.2020.127670. Epub 2020 Nov 6.

Authors

Martín S Faillace¹, Antonio L Alves Borges Leal², Felipe Araújo de Oliveira Alcântara², Josie H L Ferreira², José P de Siqueira-Júnior³, Carlos E Sampaio Nogueira⁴, Humberto M Barreto⁵, Walter J Peláez⁶

Affiliations

¹ CONICET-INFIQC, Departamento de Fisicoquímica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre s/n, Pabellón Argentina, Ciudad Universitaria, Córdoba X5000HUA, Argentina.
² Federal University of Piaui, Laboratory of Research in Microbiology, Campus University Ministry Petrônio Portella, Ininga Neighborhood, Teresina, Piaui 64049-901, Brazil.
³ Laboratory of Genetics of Microorganisms, Federal University of Paraiba, Joao Pessoa, Paraiba, Brazil.
⁴ Department of Physics, Regional University of Cariri, Crato, Ceará, Brazil.
⁵ Federal University of Piaui, Laboratory of Research in Microbiology, Campus University Ministry Petrônio Portella, Ininga Neighborhood, Teresina, Piaui 64049-901, Brazil. Electronic address: hmbarreto@ufpi.edu.br.
⁶ CONICET-INFIQC, Departamento de Fisicoquímica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre s/n, Pabellón Argentina, Ciudad Universitaria, Córdoba X5000HUA, Argentina. Electronic address: walter.pelaez@unc.edu.ar.

PMID: 33161124
DOI: 10.1016/j.bmcl.2020.127670

Abstract

Searching for new alternatives to antibiotic treatments is crucial to surmount the multidrug-resistant bacteria. In this work, the antimicrobial activity of synthetic imidazolidines was evaluated as well as their modulating effect on the resistance to fluoroquinolones in a S. aureus strain (SA-1199B), which overexpresses the norA gene that encodes the NorA efflux pump. Results showed weak antimicrobial activity (512 μg mL^-1) for two fluorobenzylidene derivatives against this bacterial strain, while the other benzylidene derivatives were inactive. Despite this fact, both fluorinated compounds were able to enhance the activity of norfloxacin and ciprofloxacin against SA-1199B up to 6.4- and 3.2-fold, respectively. In addition, both derivatives potentiated the action of ethidium bromide against this strain, suggesting that the modulating effect probably involves the inhibition of the NorA efflux pump, which is in concordance with the fluorimetic assays and molecular docking analyses performed in this work.

Keywords: Antibiotics; Antimicrobial activity; Imidazolidines; NorA efflux pump; Staphylococcus aureus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Imidazolidines / chemical synthesis
Imidazolidines / chemistry
Imidazolidines / pharmacology*
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Multidrug Resistance-Associated Proteins / metabolism
Staphylococcus aureus / drug effects*
Staphylococcus aureus / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
Imidazolidines
Multidrug Resistance-Associated Proteins
NorA protein, Staphylococcus