Publications by authors named "José P Siqueira-Junior"

32 Publications

Enhancement of the antibiotic activity by quercetin against Staphylococcus aureus efflux pumps.

J Bioenerg Biomembr 2021 Apr 8;53(2):157-167. Epub 2021 Mar 8.

Laboratory of Semi-Arid Bioprospecting (Lab-Bioprospec), Department of Biological Chemistry, DQB/URCA, Crato, Ceará, Brazil.

The objective of this work was to evaluate the inhibitory effect of quercetin on S. aureus Efflux Pumps. The MIC of Quercetin was evaluated through the broth microdilution method, as well as the Efflux Pump inhibition assay through the method of reducing the antibiotic minimum inhibitory concentration as well as that of ethidium bromide. The in silico approach through bioinformatics was performed to demonstrate the molecular mechanism of interaction of the substrate and the binding cavity. The Quercetin inhibition concentration was not clinically relevant. With respect to the reversal of bacterial resistance effect by efflux pump inhibition, this effect was observed with the strains carrying the TetK and NorA pumps. Regarding the interaction between the Quercetin complex and the NorA pump, the extra stability was provided by hydrogen bonds produced by the hydroxyl group.
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http://dx.doi.org/10.1007/s10863-021-09886-4DOI Listing
April 2021

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

Bioorg Med Chem Lett 2021 01 6;31:127670. Epub 2020 Nov 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:

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) 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.
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http://dx.doi.org/10.1016/j.bmcl.2020.127670DOI Listing
January 2021

Inhibition of Efflux Pumps by Monoterpene (α-pinene) and Impact on Resistance to Tetracycline and Erythromycin.

Curr Drug Metab 2021 ;22(2):123-126

Department of Biological Chemistry, URCA, Crato, Brazil.

Introduction: Infectious diseases have been responsible for an increasing number of deaths worldwide. Staphylococcus aureus has been recognized as one of the most notable causative agents of severe infections, while efflux pump (EP) expression is one of the main mechanisms associated with S. aureus resistance to antibiotics.

Objective: This study aimed to investigate the potential of α-pinene as an efflux pump inhibitor in species of S. aureus carrying the TetK and MrsA proteins.

Methods: The minimum inhibitory concentrations (MIC) of α-pinene and other efflux pump inhibitors were assessed using serial dilutions of each compound at an initial concentration above 1024 μg/mL. Solutions containing culture medium and bacterial inoculums were prepared in test tubes and subsequently transferred to 96-well microdilution plates. The modulation of ethidium bromide (EtBr) and antibiotics (tetracycline and erythromycin) was investigated through analysis of the modification in their MICs in the presence of a subinhibitory concentration of α-pinene (MIC/8). Wells containing only culture medium and bacterial inoculums were used as negative control. Carbonyl cyanide m-chlorophenylhydrazone (CCCP) was used as a positive control.

Results: The MIC of ethidium bromide against S. aureus strains RN-4220 and IS-58 was reduced by association with α-pinene. This monoterpene potentiated the effect of tetracycline against the IS-58 strain but failed in modulating the antibacterial effect of erythromycin against RN-4220, suggesting a selective inhibitory effect on the TetK EP by α- pinene.

Conclusion: In conclusion, α-pinene has promising effects against S.aureus strains, which should be useful in the combat of antibacterial resistance associated with EP expression. Nevertheless, further research is required to fully characterize its molecular mechanism of action as an EP inhibitor.
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http://dx.doi.org/10.2174/1389200221999200730212721DOI Listing
January 2021

Effect of Vitamin K Inhibiting the Function of NorA Efflux Pump and Its Gene Expression on .

Membranes (Basel) 2020 Jun 25;10(6). Epub 2020 Jun 25.

Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Brazil.

Resistance to antibiotics has made diseases that previously healed easily become more difficult to treat. is an important cause of hospital-acquired infections and multi-drug resistant. NorA efflux pump, present in bacteria , is synthesized by the expression of the gene. Menadione, also known as vitamin K, is one of the synthetic forms of vitamin K. Therefore, the aim of this study is to verify the menadione effect on efflux inhibition through NorA pump gene expression inhibition and assess the effects of menadione in bacterial membrane. The effect of menadione as an efflux pump inhibitor (EPI) was evaluated by the microdilution method, fluorimetry, electron microscopy, and by RT-qPCR to evaluate gene expression. In the molecular docking, association with menadione induces increased fluorescence intensity. Menadione was observed (100% of the clusters) interacting with residues ILE12, ILE15, PHE16, ILE19, PHE47, GLN51, ALA105, and MET109 from NorA. The results showed the gene had its expression significantly diminished in the presence of menadione. The simulation showed that several menadione molecules were able to go through the bilayer and allow the entry of water molecules into the hydrophobic regions of the bilayer. When present within membranes, menadione may have caused membrane structural changes resulting in a decline of the signaling pathways involved in expression. Menadione demonstrated to be an efflux pump inhibitor with dual mechanism: affecting the efflux pump by direct interaction with protein NorA and indirectly inhibiting the gene expression, possibly by affecting regulators present in the membrane altered by menadione.
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http://dx.doi.org/10.3390/membranes10060130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345349PMC
June 2020

Modulation of the Drug Resistance by Mart. Extract, Ethyl Acetate Fraction and Morelloflavone/Volkensiflavone (Biflavonoids) in Strains Overexpressing Efflux Pump Genes.

Curr Drug Metab 2021 ;22(2):114-122

Laboratory of Research in Microbiology, Federal University of Piaui, Teresina PI, Brazil.

Background: Microbial resistance to antibiotics is a global public health problem, which requires urgent attention. Platonia insignis is a native species from the eastern Brazilian Amazon, used in the treatment of burns and wounds.

Objectives: To evaluate the antimicrobial activity of the hydroalcoholic extract of P. insignis (PIHA), the ethyl acetate fraction (PIAE), and its subfraction containing a mixture of biflavonoids (BF). Moreover, the effect of these natural products on the antibiotic activity against S. aureus strains overexpressing efflux pump genes was also evaluated.

Methods: Minimal inhibitory concentrations were determined against different species of microorganisms. To evaluate the modulatory effect on the Norfloxacin-resistance, the MIC of this antibiotic was determined in the absence and presence of the natural products at subinhibitory concentrations. Inhibition of the EtBr efflux assays were conducted in the absence or presence of natural products.

Results: PIHA showed a microbicidal effect against S. aureus and C. albicans, while PIAE was bacteriostatic for S. aureus. PIAE and BF at subinhibitory concentrations were able to reduce the MIC of Norfloxacin acting as modulating agents. BF was able to inhibit the efflux of EtBr efflux in S. aureus strains overexpressing specific efflux pump genes.

Conclusion: P. inignisis, a source of efflux pump inhibitors, including volkensiflavone and morelloflavone, which were able to potentiate the Norfloxacin activity by NorA inhibition, being also able to inhibit QacA/B, TetK and MsrA. Volkensiflavone and morelloflavone could be used as an adjuvant in the antibiotic therapy of multidrug resistant S. aureus strains overexpressing efflux pumps.
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http://dx.doi.org/10.2174/1389200221666200523155617DOI Listing
January 2021

Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors.

ChemMedChem 2020 04 18;15(8):716-725. Epub 2020 Mar 18.

Department of Biological Sciences, State University of Paraiba, Laboratory of Synthesis and Drug Delivery, João Pessoa, PB, Brazil.

2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8- and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose- and time-dependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.
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http://dx.doi.org/10.1002/cmdc.201900688DOI Listing
April 2020

In vitro e in silico evaluation of the inhibition of Staphylococcus aureus efflux pumps by caffeic and gallic acid.

Comp Immunol Microbiol Infect Dis 2018 Apr 12;57:22-28. Epub 2018 Mar 12.

Laboratory of Semi-Arid Bioprospecting (Lab-Bioprospec), Department of Biological Chemistry/CCBS/URCA, Ceará, Brazil. Electronic address:

Staphylococcus aureus has been reported as one of the most difficult to treat. In the search for new treatment alternatives, isolated plant substances such as phenolic compounds, have demonstrated the ability to reverse bacterial resistance. The present study aims to evaluate the inhibitory action of caffeic acid and gallic acid on efflux pumps from S. aureus resistant strains. The broth microdilution assay was carried out to obtain the MICs of caffeic acid and gallic acid while the efflux pump inhibition test was assessed through the reduction of the minimum inhibitory concentration of the antibiotic and ethidium bromide. In addition, in silico theoretical parameters were analyzed to determine the theoretical efficacy of the compound and its free energy of interaction. In the results, the inhibition concentration of the two compounds did not certify clinical relevance with 1024 μg/mL for all strains. In the efflux pump inhibition effect, caffeic acid inhibited the MrsA pumps of the strain RN-4220 and NorA of the strain 1199B. Caffeic acid showed greater efficacy in the docking model, in agreement with the demonstrated experimental efficacy. Isolated compounds can be indicated as efficient options in the inhibition of resistance mechanisms.
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http://dx.doi.org/10.1016/j.cimid.2018.03.001DOI Listing
April 2018

Inhibition of the essential oil from Chenopodium ambrosioides L. and α-terpinene on the NorA efflux-pump of Staphylococcus aureus.

Food Chem 2018 Oct 22;262:72-77. Epub 2018 Apr 22.

Laboratory of Farmatoxicological Prospecting of Bioactive Products (BIOFARMATOX), Department of Antibiotics, Federal University of Pernambuco (UFPE), Recife, Brazil.

This study was carried out to test the essential oil from C. ambrosioides leaves and its main constituent, α-Terpinene, in an antibacterial activity assay. As well, it was evaluated ability reduce resistance to norfloxacin and ethidium bromide was compared the Staphylococcus aureus 1199B whith 1199 wild type strain. The MIC of the C. ambrosioides essential oil and α-Terpinene were determined by microdilution method. The MIC of the essential oil and α-Terpinene presented a value ≥ 1024 μg/mL. However, when associated with antibacterials, the essential oil from C. ambrosioides leaves significantly reduced the MIC of antibiotics and ethidium bromide, characterizing an efflux pump inhibition. The C. ambrosioides essential oil, despite having no direct antibacterial activity against the S. aureus 1199B strain, showed a potentiating action when associated with antibacterial agents, this being attributed to an inhibition of efflux pumps.
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http://dx.doi.org/10.1016/j.foodchem.2018.04.040DOI Listing
October 2018

Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps.

Bioorg Chem 2017 10 12;74:197-200. Epub 2017 Aug 12.

Evolutionary Biology and Bioinformatics Laboratory (LABBE), Department of Genetics|CCB|UFPE, Brazil.

The widespread use of antibiotics created selective pressure for the emergence of strains that would persist despite antibiotic toxicity. The bacterial resistance mechanisms are several, with efflux pumps being one of the main ones. These pumps are membrane proteins with the function of removing antibiotics from the cell cytoplasm. Due to this importance, the aim of this work was to evaluate the inhibitory effect of tannic acid against efflux pumps expressed by the Staphylococcus aureus RN4220 and IS-58 strains. The efflux pump inhibition was assayed using a sub-inhibitory concentration of efflux pump standard inhibitors and tannic acid (MIC/8), observing their capacity to decrease the MIC of Ethidium bromide (EtBr) and antibiotics due the possible inhibitory effect of these substances. The MICs of EtBr and antibiotics were significantly different in the presence of tannic acid, indicating the inhibitory effect of this product against efflux pumps of both strains. These results indicate the possible usage of tannic acid asan inhibitor and an adjuvant in the antibiotic therapy against multidrug resistant bacteria (MDR).
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http://dx.doi.org/10.1016/j.bioorg.2017.08.004DOI Listing
October 2017

Inhibitory effects of flavonoids on biofilm formation by Staphylococcus aureus that overexpresses efflux protein genes.

Microb Pathog 2017 Jun 29;107:193-197. Epub 2017 Mar 29.

Laboratório de Genética de Microrganismos, Departamento de Biologia Molecular, Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil.

This study evaluated the efficacy of glycone (myricitrin, hesperidin and phloridzin) and aglycone flavonoids (myricetin, hesperetin and phloretin) in inhibiting biofilm formation by Staphylococcus aureus RN4220 and S. aureus SA1199B that overexpress the msrA and norA efflux protein genes, respectively. The minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC - defined as the lowest concentration that resulted in ≥50% inhibition of biofilm formation) of flavonoids were determined using microdilution in broth procedures. The flavonoids showed MIC >1024 μg/mL against S. aureus RN4220 and S. aureus SA1199B; however, these compounds at lower concentrations (1-256 μg/mL) showed inhibitory effects on biofilm formation by these strains. Aglycone flavonoids showed lower MBIC values than their respective glycone forms. The lowest MBIC values (1 and 4 μg/mL) were observed against S. aureus RN4220. Myricetin, hesperetin and phloretin exhibited biofilm formation inhibition >70% for S. aureus RN4220, and lower biofilm formation inhibition against S. aureus SA1199B. These results indicate that sub-MICs of the tested flavonoids inhibit biofilm formation by S. aureus strains that overexpress efflux protein genes. These effects are more strongly established by aglycone flavonoids.
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http://dx.doi.org/10.1016/j.micpath.2017.03.033DOI Listing
June 2017

Inhibition of the TetK efflux-pump by the essential oil of Chenopodium ambrosioides L. and α-terpinene against Staphylococcus aureus IS-58.

Food Chem Toxicol 2017 Nov 24;109(Pt 2):957-961. Epub 2017 Feb 24.

Laboratory of Microbiology and Molecular Biology, Department of Chemical Biology, Regional University of Cariri, Crato, Brazil.

The use of natural products is crucial to suppress the development of these micro-organisms and to reduce the concentration necessary to inhibit these microrganisms, reducing the toxicity risks also. In this study, the essential oil from Chenopodium ambrosioides Leaves and its main constituent α-Terpinene were used in the antibacterial and potentiating activity of antibiotics and ethidium bromide assays, against the bacterial strains Staphylococcus aureus IS-58, carriers of efflux pumps. The Minimum Inhibitory Concentration (MIC) was determined using a microdilution method. The capacity of the aforementioned was also tested in combination with tetracycline and ethidium bromide, with the aim of improving the activity of the antibacterials. The MIC of the C. ambrosioides L. essential oil and of α-Terpinene were above 1024 μg/mL, comprising a clinically irrelevant value. However, when associated with the antibiotics, the C. ambrosioides L. essential oil, significantly decreased the MIC of tetracycline and ethidium bromide. The efflux pump is the only mechanism the bacteria possesses to reduce the toxicity of ethidium bromide, and thus this reduction in the MIC demonstrates that the C. ambrosioides L. essential oil is an effective option in the inhibition of the efflux pump present in these micro-organisms.
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http://dx.doi.org/10.1016/j.fct.2017.02.031DOI Listing
November 2017

Modulation of the antibiotic activity against multidrug resistant strains of coumarins isolated from Rutaceae species.

Microb Pathog 2017 Mar 19;104:151-154. Epub 2017 Jan 19.

Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, João Pessoa, Brazil. Electronic address:

The first occurrences and dissemination of resistant microorganisms led to the inefficacy of many antibiotics, available in the market nowadays, therefore, the search for new substances with antimicrobial activity from natural sources has gained a great importance. The purpose of this work is to evaluate the antibacterial activity and modulation of drug resistance in Staphylococcus aureus by coumarins such as bergapten, xantotoxin, isopimpinellin and imperatorin obtained from two Rutaceae species (Metrodorea mollis and Pilocarpus spicatus). The antimicrobial activity was assessed based on the minimum inhibitory concentration (MIC), using the microdilution method. The MIC was >256 g/mL for all coumarins tested. Regarding the modulation of drug resistance assay, the isopimpinellin reducted the MIC of erytromicin by 4 times, whereas imperatorin exhibited the best result, reducing the MIC of tetracycline (2 times), erytomicin (4 times) and norfloxacin (4 times). By reducing the MIC of ethidium bromide, the imperatorin is consider in fact, as a putative efflux pump inhibitor of bacteria.
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http://dx.doi.org/10.1016/j.micpath.2017.01.028DOI Listing
March 2017

Action of cholecalciferol and alpha-tocopherol on Staphylococcus aureus efflux pumps.

EXCLI J 2016 29;15:315-22. Epub 2016 Apr 29.

Department of Physiology/UFS, Brazil.

Alpha-tocopherol is one the most abundant and biologically active isoforms of vitamin E. This compound is a potent antioxidant and one of most studied isoforms of vitamin E. Vitamin D3 (cholecalciferol) is an important nutrient for calcium homeostasis and bone health, that has also been recognized as a potent modulator of the immune response. Methicillin-resistant Staphylococcus aureus (MRSA) is the most important causative agent of both nosocomial and community-acquired infections. The aim of this study was to evaluate the inhibitory effect of alpha-tocopherol and cholecalciferol on both S. aureus and multidrug resistant S. aureus efflux pumps. The RN4220 strain has the plasmid pUL5054 that is the carrier of gene that encodes the macrolide resistance protein (an efflux pump) MsrA; the IS-58 strain possesses the TetK tetracycline efflux protein in its genome and the 1199B strain resists to hydrophilic fluoroquinolones via a NorA-mediated mechanism. The antibacterial activity was evaluated by determining the Minimal Inhibitory Concentration (MIC) and a possible inhibition of efflux pumps was associated to a reduction of the MIC. In this work we observed that in the presence of the treatments there was a decrease in the MIC for the RN4220 and IS-58 strains, suggesting that the substances presented an inhibitory effect on the efflux pumps of these strains. Significant efforts have been done to identify efflux pump inhibitors (EPIs) from natural sources and, therefore, the antibacterial properties of cholecalciferol and alpha-tocopherol might be attributed to a direct effect on the bacterial cell depending on their amphipathic structure.
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http://dx.doi.org/10.17179/excli2016-277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897629PMC
June 2016

Tannic Acid as a Potential Modulator of Norfloxacin Resistance in Staphylococcus Aureus Overexpressing norA.

Chemotherapy 2016 3;61(6):319-22. Epub 2016 May 3.

Background: Tannins have shown inhibitory effects against pathogenic bacteria, and these properties make tannins potential modifying agents in bacterial resistance.

Methods: The minimum inhibitory concentration (MIC) of tannic acid (TA), gallic acid (GA) and norfloxacin (Nor) against Staphylococcus aureus SA-1119 (NorA-effluxing strain) was determined using broth microdilution tests. To assess the modulation of antibiotic resistance, the MIC of Nor was determined in growth media with or without TA or GA at a subinhibitory concentration (1/4 MIC). The checkerboard method was performed to obtain the fractional inhibitory concentration index (FICI) for the combined application of TA and Nor.

Results: TA displayed a weak inhibitory effect (MIC 512 μg/ml) against S. aureus SA-1119, while no inhibitory effect was displayed by GA (MIC >512 μg/ml). However, when TA was tested at a subinhibitory concentration in combination with Nor, the MIC of Nor against S. aureus SA-1119 decreased from 128 to 4 μg/ml (32-fold); this effect was not observed for GA. In the checkerboard assay, the MIC of TA and Nor decreased from 512 to 128 μg/ml (4-fold) and from 128 to 8 μg/ml (16-fold), respectively. The combination of TA and Nor presented an FICI as low as 0.31, which indicates a synergistic interaction.

Conclusions: TA is a potential agent for increasing the clinical efficacy of Nor to control resistant S. aureus.
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http://dx.doi.org/10.1159/000443495DOI Listing
February 2017

Evaluation of the tannic acid inhibitory effect against the NorA efflux pump of Staphylococcus aureus.

Microb Pathog 2016 Aug 4;97:9-13. Epub 2016 Apr 4.

Evolutionary Biology and Bioinformatics Laboratory (LABBE), Department of Genetics, CCB, UFPE, Brazil.

During the early periods of antibiotic usage, bacterial infections were considered tamed. However, widespread antibiotic use has promoted the emergence of antibiotic-resistant pathogens, including multidrug resistant strains. Active efflux is a mechanism for bacterial resistance to inhibitory substances, known simply as drug efflux pumps. The bacterium Staphylococcus aureus is an important pathogenic bacterium responsible for an array of infections. The NorA efflux pump has been shown to be responsible for moderate fluoroquinolone resistance of S. aureus. The inhibition of the efflux pump was assayed using a sub-inhibitory concentration of standard efflux pump inhibitors and tannic acid (MIC/8), where its capacity to decrease the MIC of Ethidium bromide (EtBr) and antibiotics due to the possible inhibitory effect of these substances was observed. The MICs of EtBr and antibiotics were significantly reduced in the presence of tannic acid, indicating the inhibitory effect of this agent against the efflux pumps of both strains causing a three-fold reduction of the MIC when compared with the control. These results indicate the possible usage of tannic acid as an adjuvant in antibiotic therapy against multidrug resistant bacteria (MDR).
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http://dx.doi.org/10.1016/j.micpath.2016.04.003DOI Listing
August 2016

The Essential Oil from Origanum vulgare L. and Its Individual Constituents Carvacrol and Thymol Enhance the Effect of Tetracycline against Staphylococcus aureus.

Chemotherapy 2014 13;60(5-6):290-3. Epub 2015 May 13.

Laboratório de Genética de Microrganismos, Departamento de Biologia Molecular, Centro de Ciências da Saúde, Universidade Federal da Paraíba, João Pessoa, Brasil.

Background: In an ongoing project to evaluate essential oils as modulators of antibiotic resistance, the essential oil from Origanum vulgare L. (OVEO), as well as its individual constituents carvacrol (CAR) and thymol (THY), were investigated using Staphylococcus aureus strains possessing efflux mechanisms of resistance to norfloxacin, erythromycin and tetracycline.

Methods: The minimum inhibitory concentration (MIC) values of the antibiotics were determined by agar dilution method, in the absence and in the presence of subinhibitory concentrations of OVEO, CAR or THY.

Results: Along with relevant antistaphylococcal activity, OVEO, CAR and THY modulated the activity of tetracycline, i.e. in combination with antibiotics a reduction in the MIC was observed (up to fourfold).

Conclusions: The results presented here represent, as far as we know, the first report of OVEO, CAR and THY as putative efflux pump inhibitors. Broadly, these findings indicate that essential oils could serve as potential sources of compounds capable of modulating drug resistance.
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http://dx.doi.org/10.1159/000381175DOI Listing
April 2016

Light-mediated antibacterial activity of Lippia origanoides H.B.K. in vitro.

Photochem Photobiol Sci 2014 Dec 31;13(12):1650-4. Epub 2014 Oct 31.

Laboratory of Research in Microbiology, Department of Parasitology and Microbiology, Federal University of Piauí, Teresina (PI), Brazil.

An ethanol extract and different partition fractions obtained from Lippia origanoides H.B.K. were assayed for light-mediated activity against strains of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Identical assays were conducted with and without exposure to UV-A (400-315 nm) light to test for light enhanced activity. The ethanol extract and dichloromethane fraction showed light-mediated activity against the S. aureus strain, but not against the E. coli strain. The dichloromethane fraction was more active than the ethanol extract. Naringenin did not display light-mediated activity against the tested bacteria, indicating that the light-mediated antimicrobial activity of the dichloromethane fraction is not due to its major component. The results represent the first report of light-mediated antimicrobial activity of Lippia origanoides and show that its phytochemicals could be used as light-mediated antimicrobial agents.
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http://dx.doi.org/10.1039/c4pp00334aDOI Listing
December 2014

Modulation of the UVB-induced lethality by furocoumarins in Staphylococcus aureus.

J Photochem Photobiol B 2014 Jan 26;130:260-3. Epub 2013 Nov 26.

Departamento de Biologia Molecular, Universidade Federal da Paraíba, João Pessoa, Brazil.

Furocumarins (FCs) are photoactive compounds capable of binding to DNA, and once excited by UVA light (∼365nm), they form photoadducts which can lead to mutagenicity and lethality. However, the biological effects of FCs combined with UVB light (312nm) is still little investigated. In the present study, the lethal effect of UVB light alone and combined with different concentrations of 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and 3-carbethoxypsoralen (3-CPs) was evaluated in a strain of Staphylococcus aureus. 8-MOP-UVB and TMP-UVB were more effective in inducing lethality compared to UVB alone, indicating that these FCs act as photosensitizing agents for UVB. The increase in concentration of 8-MOP resulted in a greater mortality. On the contrary, a decrease in mortality was found with an increase in TMP concentration. 3-CPs protected bacteria against damage induced by UVB, which can be attributed to the inhibition of cyclobutyl pyrimidine dimer formation. The different modulatory effects on lethality induced by UVB shown by the FCs tested could be related to differences in the specificity of each compound for particular nucleotide sequences, as well as other chemical characteristics of each molecule could influence the number and types of adducts formed, contributing to the photosensitizing or photoprotective effects observed.
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http://dx.doi.org/10.1016/j.jphotobiol.2013.11.012DOI Listing
January 2014

Modulation of the norfloxacin resistance in Staphylococcus aureus by Cordia verbenaceae DC.

Indian J Med Res 2013 Jan;137(1):178-82

Laboratório de Microbiologia e Biologia Molecular, Universidade Regional do Cariri, Crato, Ceara, Brazil.

Background & Objectives: Several chemical compounds isolated from natural sources have antibacterial activity and some enhance the antibacterial activity of antibiotics reversing the natural resistance of bacteria to certain antibiotics. In this study, the hexane and methanol extract of Cordia verbenaceae were assessed for antibacterial activity alone and combinated with norfloxacin against the Staphylococcus aureus strain SA1199B.

Methods: The minimum inhibitory concentration (MIC) of extracts was assayed using microdilution assay and the modulatory activity was evaluated using plate diffusion assay.

Results: The MIC observed varied between 256 to >1024 μg/ml. However, the antibiotic activity of norfloxacin was enhanced in the presence of subinhibitory concentrations of hexane extract of C. verbenaceae (HECV). INTERPRETATIONS & CONCLUSIONS: Our results indicate that Cordia verbenaceae DC. can be a source of plant derived products with antibiotic modifying activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657884PMC
January 2013

Modulation of the norfloxacin resistance in Staphylococcus aureus by Croton campestris A. and Ocimum gratissimum L.

Biomedica 2011 Oct-Dec;31(4):608-12

Laboratório de Microbiologia e Biologia Molecular, Universidade Regional do Cariri, Crato, CE, Brasil.

Introduction: Some species of Staphylococcus are often recognized as etiological agents of many animal and human opportunistic infections. This study is the first test of change in resistance of antibiotic activity by Croton campestris A. and Ocimum gratissimum L. against multiresistant strains of Staphylococcus aureus.

Objective: In this study, the hexane and methanol extract of Croton campestris A. and Ocimum gratissimum L. was tested for antibacterial activity alone and in combination with norfloxacin against the strain SA1199B.

Materials And Methods: The minimum inhibitory concentration (MIC) and the modulatory effect of extracts was assayed using microtitre assay.

Results: By the fact of the MIC observed was not clinically relevant (MIC= 512 to ≥1.024 µg/ml), the antibiotic activity of norfloxacin was enhanced when this antibiotic was combined with sub-inhibitory concentrations of extracts, mainly the hexane extracts.

Conclusions: These results indicate that the assayed extracts present compounds that can be used as a putative efflux pump inhibitor, indicating that Croton campestris A. and Ocimum gratissimum L. can be a source of plant derived products with antibiotic modifier activity.
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http://dx.doi.org/10.1590/S0120-41572011000400016DOI Listing
October 2012

In vitro additive effect of Hyptis martiusii in the resistance to aminoglycosides of methicillin-resistant Staphylococcus aureus.

Pharm Biol 2010 Sep;48(9):1002-6

Laboratory of Research in Natural Products, University of the Region of Cariri, Crato, CE, Brazil.

Context: Bacterial infectious agents represent a risk to populations, where they are responsible for the high morbidity and mortality. In combating these pathogens, our main line of defense is the use of antibiotics. However, the indiscriminate use of these drugs select resistant strains to these same drugs.

Objective: In this study the ethanol extract of Hyptis martiusii Benth. (EEHM) (Lamiaceae) was tested for its antimicrobial activity against aminoglycoside multi-resistant Staphylococcus aureus (MRSA).

Materials And Methods: In this study, the ethanol extract of H. martiusii was prepared and tested with chlorpromazine for its antimicrobial activity using the microdilution method. Chlorpromazine and the ethanol extract were used alone and also in combination with aminoglycosides against a MRSA strain resistant to these antibiotics to determine the participation of efflux systems in resistance mechanisms. The FIC index was calculated and evaluated by the checkerboard method.

Results: A potentiating effect between this extract and aminoglycosides was demonstrated. Similarly, a potentiating effect of chlorpromazine with kanamycin was detected, indicating the involvement of an efflux system in the resistance to this aminoglycoside. The checkerboard method with combinations of aminoglycosides and EEHM demonstrated additive effect with kanamycin and gentamicin. It is therefore suggested that extracts from H. martiusii could be used as a source of plant-derived natural products with resistance- modifying activity.

Conclusion: This is the first report about the modifying antibiotic activity of Hyptis martiusii, constituting a new approach against bacterial resistance to antibiotics as aminoglycosides.
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http://dx.doi.org/10.3109/13880200903382686DOI Listing
September 2010

Potentiation of antibiotic activity by Eugenia uniflora and Eugenia jambolanum.

J Med Food 2010 Aug;13(4):1024-6

Laboratory of Research in Natural Products, Center of Biological Sciences and Health, University of the Region of Cariri, Crato, Brazil.

This is the first report about the modifying antibiotic activity of Eugenia uniflora L. and Eugenia jambolanum L. In this study the ethanol extract of E. uniflora and E. jambolanum was tested for their antimicrobial activity against strains of Escherichia coli. The growth of the two strains of E. coli bacteria tested was not inhibited in a clinically relevant form by the extract. The minimal inhibitory concentration was >or=1,024 microg/mL for both strains of E. coli assayed. Synergism between this extract and gentamicin was demonstrated. In the same extract synergism was observed between chlorpromazine and kanamycin and between amikacin and tobramycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides. It is therefore suggested that extracts from E. uniflora L. and E. jambolanum L. could be used as a source of plant-derived natural products with modifying antibiotic activity to gentamicin.
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http://dx.doi.org/10.1089/jmf.2009.0158DOI Listing
August 2010

Effect of Momordica charantia L. in the resistance to aminoglycosides in methicilin-resistant Staphylococcus aureus.

Comp Immunol Microbiol Infect Dis 2010 Dec 3;33(6):467-71. Epub 2009 Sep 3.

Laboratory of Research in Natural Products, University of the Region of Cariri, Crato (CE), Brazil.

In this study the ethanol extract (EEMC) of Momordica charantia L. (Cucurbitaceae) was tested for its modifying antibiotic activity against a MRSA strain. The growth of an MRSA (SA358) in the absence and presence of aminoglycosides was evaluated. A potentiating effect between this extract and all aminoglycosides was demonstrated. Similarly, the same effect was shown by chlorpromazine on kanamycin, gentamicin and neomycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides. Extracts from M. charantia could be used as a source of plant-derived natural products with resistance-modifying activity. This is the first report about the modifying antibiotic activity of M. charantia, constituting a new weapon against multi-resistant bacteria such as MRSA.
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http://dx.doi.org/10.1016/j.cimid.2009.08.001DOI Listing
December 2010

In vitro interference of Hyptis martiusii Benth. & chlorpromazine against an aminoglycoside-resistant Escherichia coli.

Indian J Med Res 2009 May;129(5):566-8

Departamento de Ciências Biológicas, Centro de Ciências Biológicas e da Saúde, Universidade Regional do Cariri Crato, Crato (CE), Brazil.

The antibacterial and synergistic activity of the ethanol extract from Hyptis martiusii Benth. was assayed by microdillution. The growth of two isolates of Escherichia coli tested was inhibited by the extract. The minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) values ranged from 512 and >1024 microg/ml for the E. coli 27 and 1024 and > 1024 microg/ml for the E. coli ATCC8539, respectively. A synergism between this extract and all aminoglycosides assayed was demonstrated. In the same form synergism between chlorpromazine and kanamycin, amikacin and tobramycin was observed, indicating the involvement of an efflux system. Extracts from H. martiusii could be used as a source of plant derived natural products with modifying antibiotic activity and these products may interact and affect multidrug resistance systems (MDR) as efflux pumps.
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May 2009

Increasing of the aminoglicosyde antibiotic activity against a multidrug-resistant E. coli by Turnera ulmifolia L. and chlorpromazine.

Biol Res Nurs 2010 Apr 24;11(4):332-5. Epub 2009 Jul 24.

Laboratory of Research in Natural Products, Department of Biological Sciences, University of the Region of Cariri, Rua Cel. Antonio Luis 1161, Crato, CE, Brazil.

In this study, an ethanol extract of Turnera ulmifolia L. (EETU) and chlorpromazine (CPZ) were tested for their antimicrobial activity alone or in combination with conventional antibiotics against two strains of Escherichia coli (E. coli). The growth of neither E. coli strain was inhibited by the extract. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration values were > or =1 mg/ml for both the strains of E. coli. However, the extract did increase the antimicrobial effects of amikacin, neomycin, and tobramycin. A similar effect of CPZ on amikacin, kanamycin, and tobramycin indicated the involvement of an efflux system in the resistance to these aminoglycosides. Results suggest that extracts from T. ulmifolia could be used as a plant-derived natural product with resistance-modifying activity, constituting a new weapon against bacterial resistance to antibiotics.
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http://dx.doi.org/10.1177/1099800409340052DOI Listing
April 2010

Potentiating effect of Mentha arvensis and chlorpromazine in the resistance to aminoglycosides of methicillin-resistant Staphylococcus aureus.

In Vivo 2009 Mar-Apr;23(2):287-9

Laboratory of Research in Natural Products, Department of Biological Chemistry, Center of Biological Sciences and Health, University of the Region of Cariri, Crato, Brazil.

Background: This is the first report testing the antibiotic resistance-modifying activity of Mentha arvensis against MRSA (methicillin-resistant Staphylococcus aureus).

Materials And Methods: In this study an ethanol extract of Mentha arvensis L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with conventional antibiotics against MRSA strains.

Results: A potentiating effect of this extract on gentamicin, kanamycin and neomycin was demonstrated. Similarly, a potentiating effect of chlorpromazine on the same aminoglycosides was observed, indicating the involvement of an efflux system in the resistance to these antibiotics.

Conclusion: It is therefore suggested that extracts from M. arvensis could be used as a source of plant-derived natural products with resistance-modifying activity, such as in the case of aminoglycosides, constituting a new weapon against bacterial resistance to antibiotics, as with chlorpromazine.
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July 2009

In vitro phototoxic activity of Eugenia jambolana L. and Hyptis martiusii Benth.

J Photochem Photobiol B 2009 Jul 12;96(1):63-5. Epub 2009 Apr 12.

Laboratory of Research in Natural Products, Center of Biological Sciences and Health, University of the Region of Cariri, Crato (CE), Brazil.

Ethanol extracts from Hyptis martiusii and Eugenia jambolana were assayed for light-mediated activity against strains of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Duplicate assays were conducted with and without exposure to UV-A radiation to test for light-activated or light-enhanced activity. Both extracts showed activity against at least two bacterial strains, but H. martiusii was the most active extract, being active against all strains of S. aureus and E. coli. The results represent a first report of the light-mediated antimicrobial activities of H. martiusii and E. jambolana and suggest that phytochemical investigations may be warranted.
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http://dx.doi.org/10.1016/j.jphotobiol.2009.04.002DOI Listing
July 2009

Modulation of drug resistance in Staphylococcus aureus by a kaempferol glycoside from Herissantia tiubae (Malvaceae).

Phytother Res 2009 Oct;23(10):1367-70

Departamento de Biologia Molecular, Universidade Federal da Paraíba, João Pessoa (PB), Brazil.

In an ongoing project to evaluate natural compounds isolated from plants from the Brazilian biodiversity as modulators of antibiotic resistance, kaempferol-3-O-beta-d-(6''-E-p-coumaroyl) glucopyranoside (tiliroside), isolated from Herissantia tiubae (Malvaceae) was investigated using the strain SA-1199B of Staphylococcus aureus, which overexpresses the norA gene encoding the NorA efflux protein which extrudes hydrophilic fluorquinolones and some biocides, such as benzalkonium chloride, cetrimide, acriflavine and ethidium bromide. The minimum inhibitory concentrations (MICs) of the antibiotics and biocides were determined by the microdilution assay in the absence and in the presence of sub-inhibitory concentration of tiliroside. Although tiliroside did not display relevant antibacterial activity (MIC = 256 microg/mL), it modulated the activity of antibiotics, i.e. in combination with antibiotics a reduction in the MIC was observed for norfloxacin (16-fold), ciprofloxacin (16-fold), lomefloxacin (four-fold) and ofloxacin (two-fold), and an impressive reduction in the MICs for the biocides (up to 128-fold). The results presented here represent the first report of a kaempferol glycoside as a putative efflux pump inhibitor in bacteria. The present finding indicates that H. tiubae (and broadly Malvaceae) could serve as a source of plant-derived natural products that modulate bacterial resistance, i.e. a source of potential adjuvants of antibiotics.
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http://dx.doi.org/10.1002/ptr.2695DOI Listing
October 2009