Antibacterial activity and inhibition against Staphylococcus aureus NorA efflux pump by ferulic acid and its esterified derivatives

Phytochemical studies on Croton species have identified the presence of secondary metabolites responsible for a wide variety of pharmacological activities, among them antimicrobial activity. Research for new substances with antimicrobial activity derived from natural products can give a major contribution to human health worldwide by finding more efficient and fewer toxic formulas in the race against pathogenic microorganisms' resistance. Among bacterial pathogens, Staphylococcus aureus species, despite being present in the skin and nasal mucosa, can cause many infections and diseases. These opportunists reach debilitated people in hospitals and are challenging to treat. Here, we performed the structural characterization, determination of antibiotic activity, and MepA efflux pump inhibition potential against S. aureus of the chalcone (2E, 4E) -1- (2-hydroxy-3,4,6-trimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one, derived from natural products 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus and cinnamaldehyde. The chalcone was synthesized by the Claisen-Schmidt condensation. In addition, microbiological tests were performed to investigate the antibacterial activity, modulator potential, and efflux pump inhibition against the S. aureus multi-resistant strains. MIC values obtained to chalcone were not clinically relevant (MIC ≥ 1024 µg/mL). However, chalcone hampers the binding of the antibiotic to the binding site of the MepA efflux pump. It acts as a competitive inhibitor, being expelled from the bacteria in place of the antibiotic and potentiating ciprofloxacin's action against multidrug-resistant bacterial strains of K2068. Therefore, chalcone can be used as a base for substance design with antibiotic modifying activity.

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Evaluation of antibacterial activity and reversal of the NorA and MepA efflux pump of estragole against Staphylococcus aureus bacteria

Archives of Microbiology ◽

10.1007/s00203-021-02347-x ◽

2021 ◽

Author(s):

Roger Henrique Sousa da Costa ◽

Janaína Esmeraldo Rocha ◽

Thiago Sampaio de Freitas ◽

Raimundo Luiz Silva Pereira ◽

Francisco Nascimento Pereira Junior ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Efflux Pump

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Synthesis of 2-substituted indoles and evaluation of their antibacterial activity and inhibitory effects on the efflux pump of methicillin-resistant Staphylococcus aureus

Journal of Applied Pharmaceutical Science ◽

10.7324/japs.2021.120108 ◽

2022 ◽

Author(s):

Vicharn Suttinun ◽

Sirirak Jitnapa ◽

Phutdhawong Weerachai ◽

Taechowisan Thongchai ◽

Phutdhawong Waya S.

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Methicillin Resistant Staphylococcus Aureus ◽

Efflux Pump ◽

Inhibitory Effects ◽

Methicillin Resistant

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Chemical composition, antibacterial activity and effect of Rhus albida Schousb essential oil on the inhibition of NorA efflux pump in Staphylococcus aureus

South African Journal of Botany ◽

10.1016/j.sajb.2021.05.025 ◽

2021 ◽

Vol 142 ◽

pp. 19-24

Author(s):

Najoua Elhidar ◽

Bouchra Soulaimani ◽

André Goehler ◽

Jürgen A. Bohnert ◽

Abdelaziz Abbad ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Chemical Composition ◽

Essential Oil ◽

Efflux Pump

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MOLECULAR DOCKING STUDIES OF RICINUS COMMUNIS PHYTOCHEMICALS AGAINST BETA-LACTAMASE FROM ENTEROCOCCUS FAECALIS AND STAPHYLOCOCCUS AUREUS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.25421 ◽

2018 ◽

Vol 11 (7) ◽

pp. 132 ◽

Cited By ~ 1

Author(s):

Thirunavukkarasu Umaarasu ◽

Kesavaram Padmavathy ◽

Dharmalingam Thirunavukkarasu ◽

Rajesh Sv ◽

Gnanendra Shanmugam

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Molecular Docking ◽

Ferulic Acid ◽

Enterococcus Faecalis ◽

Ricinus Communis ◽

3D Structure ◽

Docking Studies ◽

Beta Lactamase ◽

And Staphylococcus Aureus

Objective: The objective of this study is to investigate the antibacterial activity of Ricinus communis phytochemicals against beta-lactamase from Enterococcus faecalis and Staphylococcus aureus through molecular docking studies. Methods: The three-dimensional (3D) structure of beta-lactamase from E. faecalis was modeled using modeler 9v9 and validated. The 3D structure of beta-lactamase from S. aureus (PDB ID: 1 GHP) was retrieved from PDB database. The 2D structures of 29 phytochemical compounds from the methanol leaf extracts of R. communis were drawn in ACD-Chemsketch and converted into 3D structures. The 3D structure of R. communis leaf compounds and cefotaxime (control) was virtually screened in the binding pockets of β-lactamase proteins from E. faecalis and S. aureus using FlexX docking program. Results: The docking studies revealed that ferulic acid and hyperoside exhibited promising minimum binding and docking energy that is closely related to the docking score of standard antibiotic cefotaxime. Conclusion: The result of the present study indicates that ferulic acid and hyperoside are potential compounds that could be effectively used in the treatment of infections caused by E. faecalis and S. aureus. However, further clinical studies are required to ascertain the antibacterial activity and potential toxic effects of ferulic acid and hyperoside in vivo.

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Evaluation of the Antibacterial Activity and Efflux Pump Reversal of Thymol and Carvacrol against Staphylococcus aureus and Their Toxicity in Drosophila melanogaster

Molecules ◽

10.3390/molecules25092103 ◽

2020 ◽

Vol 25 (9) ◽

pp. 2103 ◽

Cited By ~ 2

Author(s):

Zildene de Sousa Silveira ◽

Nair Silva Macêdo ◽

Joycy Francely Sampaio dos Santos ◽

Thiago Sampaio de Freitas ◽

Cristina Rodrigues dos Santos Barbosa ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Drosophila Melanogaster ◽

Inhibitory Concentration ◽

Efflux Pump ◽

Antibacterial Activities ◽

Broth Microdilution ◽

Microdilution Method ◽

Efflux Pump Inhibition ◽

Broth Microdilution Method

The antibacterial activity and efflux pump reversal of thymol and carvacrol were investigated against the Staphylococcus aureus IS-58 strain in this study, as well as their toxicity against Drosophila melanogaster. The minimum inhibitory concentration (MIC) was determined using the broth microdilution method, while efflux pump inhibition was assessed by reduction of the antibiotic and ethidium bromide (EtBr) MICs. D. melanogaster toxicity was tested using the fumigation method. Both thymol and carvacrol presented antibacterial activities with MICs of 72 and 256 µg/mL, respectively. The association between thymol and tetracycline demonstrated synergism, while the association between carvacrol and tetracycline presented antagonism. The compound and EtBr combinations did not differ from controls. Thymol and carvacrol toxicity against D. melanogaster were evidenced with EC50 values of 17.96 and 16.97 µg/mL, respectively, with 48 h of exposure. In conclusion, the compounds presented promising antibacterial activity against the tested strain, although no efficacy was observed in terms of efflux pump inhibition.

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1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20071699 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1699 ◽

Cited By ~ 7

Author(s):

Anton Shetnev ◽

Sergey Baykov ◽

Stanislav Kalinin ◽

Alexandra Belova ◽

Vladimir Sharoyko ◽

...

Keyword(s):

Escherichia Coli ◽

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Efflux Pump ◽

Ductal Adenocarcinoma ◽

Resistant Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Drug Resistant Bacteria ◽

Efflux Pump Inhibitors

Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.

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Inhibition of Drug Resistance of Staphylococcus aureus by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

Polish Journal of Microbiology ◽

10.33073/pjm-2019-047 ◽

2019 ◽

Vol 68 (4) ◽

pp. 477-491

Author(s):

WENJING LUAN ◽

XIAOLEI LIU ◽

XUEFEI WANG ◽

YANAN AN ◽

YANG WANG ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Combination Therapy ◽

Efflux Pump ◽

Treated Group ◽

Aureus Strain ◽

Efflux Pump Inhibitor ◽

Tnf Α ◽

Ifn Γ ◽

Number Of Bacteria

This study explored a potential treatment against methicillin-resistant Staphylococcus aureus (MRSA) infections that combines thioridazine (TZ), an efflux pump inhibitor, and miconazole (MCZ), an autolysis inducer, with the anti-microbial drug cloxacillin (CXN). In vitro, the combination treatment of TZ and MCZ significantly reduced 4096-fold (Σ (FIC) = 0.1 – 1.25) the MIC value of CXN against S. aureus. In vivo, the combination therapy significantly relieved breast redness and swelling in mice infected with either clinical or standard strains of S. aureus. Meanwhile, the number of bacteria isolated from the MRSA135-infected mice decreased significantly (p = 0.0427 < 0.05) after the combination therapy when compared to monotherapy. Moreover, the number of bacteria isolated from the mice infected with a reference S. aureus strain also decreased significantly (p = 0.0191 < 0.05) after the combination therapy when compared to monotherapy. The pathological changes were more significant in the CXN-treated group when compared to mice treated with a combination of three drugs. In addition, we found that combination therapy reduced the release of the bacteria-stimulated cytokines such as IL-6, IFN-γ, and TNF-α. Cytokine assays in serum revealed that CXN alone induced IL-6, IFN-γ, and TNF-α in the mouse groups infected with ATCC 29213 or MRSA135, and the combination of these three drugs significantly reduced IL-6, IFN-γ, and TNF-α concentrations. Also, the levels of TNF-α and IFN-γ in mice treated with a combination of three drugs were significantly lower than in the CXN-treated group. Given the synergistic antibacterial activity of CXN, we concluded that the combination of CXN with TZ, and MCZ could be developed as a novel therapeutic strategy against S. aureus.

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