Anti-inflammatory effect, antibiotic potentiating activity against multidrug-resistant strains of Escherichia coli and Staphylococcus aureus, and evaluation of antibiotic resistance mechanisms by the ibuprofen derivative methyl 2-(-4-isobutylphenyl)propanoate

Maria R Xavier; Thiago S Freitas; Raimundo L S Pereira; Emanuelle M Marinho; Paulo N Bandeira; Amanda P de Sousa; Larissa S Oliveira; Lucas Lima Bezerra; José B A Neto; Maria M C Silva; Beatriz G Cruz; Janaína E Rocha; Cristina R S Barbosa; Antonio W da Silva; Jane E S A de Menezes; Henrique D M Coutinho; Márcia M Marinho; Emmanuel S Marinho; Hélcio S Dos Santos; Alexandre M R Teixeira

doi:10.1016/j.micpath.2022.105697

Anti-inflammatory effect, antibiotic potentiating activity against multidrug-resistant strains of Escherichia coli and Staphylococcus aureus, and evaluation of antibiotic resistance mechanisms by the ibuprofen derivative methyl 2-(-4-isobutylphenyl)propanoate

Microb Pathog. 2022 Sep:170:105697. doi: 10.1016/j.micpath.2022.105697. Epub 2022 Aug 1.

Authors

Maria R Xavier¹, Thiago S Freitas¹, Raimundo L S Pereira¹, Emanuelle M Marinho², Paulo N Bandeira³, Amanda P de Sousa³, Larissa S Oliveira³, Lucas Lima Bezerra¹, José B A Neto¹, Maria M C Silva¹, Beatriz G Cruz¹, Janaína E Rocha¹, Cristina R S Barbosa¹, Antonio W da Silva⁴, Jane E S A de Menezes⁵, Henrique D M Coutinho¹, Márcia M Marinho¹, Emmanuel S Marinho⁶, Hélcio S Dos Santos⁷, Alexandre M R Teixeira⁸

Affiliations

¹ Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil.
² Department of Analytical and Physical Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil.
³ Science and Technology Centre, Course of Chemistry, State University Vale do Acaraú, Sobral, CE, Brazil.
⁴ Graduate Program in Biotechnology of the Northeast Network of Biotechnology, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil.
⁵ Graduate Program in Natural Science, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil.
⁶ Group of Theoretical Chemistry and Electrochemistry, State University of Ceará, Campus FAFIDAM, Limoeiro do Norte, CE, Brazil.
⁷ Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil; Science and Technology Centre, Course of Chemistry, State University Vale do Acaraú, Sobral, CE, Brazil; Graduate Program in Biotechnology of the Northeast Network of Biotechnology, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil; Graduate Program in Natural Science, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil.
⁸ Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil; Graduate Program in Biotechnology of the Northeast Network of Biotechnology, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil; Graduate Program in Natural Science, State University of Ceará, Campus Itaperi, Fortaleza, CE, Brazil. Electronic address: alexandre.teixeira@urca.br.

PMID: 35926804
DOI: 10.1016/j.micpath.2022.105697

Abstract

The prevalence of multidrug-resistant (MDR) bacteria and the limited efficacy of current available antibiotics cause every year approximately 700 000 deaths per year. This study aimed to evaluate the anti-inflammatory effect and antibacterial potential of the ibuprofen derivative Methyl 2-(-4-isobutylphenyl)propanoate (MET-IBU). The molecular structure of MET-IBU was confirmed by Nuclear Magnetic Resonance (NMR) and, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) spectroscopy. Our in vivo study using adult zebrafish model demonstrated that the ibuprofen derivative MET-IBU also possesses anti-inflammatory effect, and in vitro antibacterial activity assays showed that in the association of ampicillin, norfloxacin, and gentamicin with MET-IBU occurred reduction in the minimum inhibitory concentration (MIC) for MDR bacterial strains of Escherichia coli 06 and Staphylococcus aureus 10, indicating a potentiating in the growth inhibition of these pathogenic bacteria. Regarding the strain of Staphylococcus aureus K2068 (overexpressing mepA gene), a potentiation of ethidium bromide was found in the association with MET-IBU, indicating the action of this compound on the efflux pump mechanism present in this strains. This result corroborates the molecular docking study that indicated a high affinity of the MET-IBU with the MepA efflux pump. It was also noticed an antibiotic potentiating activity in the association MET-IBU with norfloxacin against strains of Staphylococcus aureus 1199B (overexpressing norA gene) when compared to the norfloxacin control. This enhanced antibiotic effect of MET-IBU is associated with a second resistance mechanism, which is due to the modification in the topoisomerase enzyme. These results bring attention to the ibuprofen derivative MET-IBU as possible candidate for the development of new options for the treatment of bacterial infections with protective anti-inflammatory action.

Keywords: Anti-inflammatory activity; Antibacterial activity; Efflux pump; Ibuprofen derivative; Multidrug-resistant bacteria.

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / genetics
Drug Resistance, Multiple, Bacterial
Escherichia coli / metabolism
Escherichia coli Infections*
Ibuprofen / pharmacology
Microbial Sensitivity Tests
Molecular Docking Simulation
Multidrug Resistance-Associated Proteins / genetics
Norfloxacin / chemistry
Norfloxacin / pharmacology
Propionates / pharmacology
Staphylococcal Infections* / drug therapy
Staphylococcal Infections* / microbiology
Staphylococcus aureus
Zebrafish

Substances

Anti-Bacterial Agents
Bacterial Proteins
Multidrug Resistance-Associated Proteins
Propionates
Norfloxacin
Ibuprofen