RESUMEN
Bacterial resistance induced by efflux pumps is a frequent concern in clinical treatments involving multi-resistant bacteria. Staphylococcus aureus is a microorganism responsible for several types of infections and has several strains carrying efflux pumps, among them are the strain 1199B (NorA overexpresser), and the strain K2068 (MepA overexpresser). In this work, four chalcones derived from Croton anisodontus with modifications in the B ring in their structures were tested regarding their ability to inhibit NorA and MepA efflux pumps. The efflux pump inhibition mechanism was tested with the ethidium bromide substrate in the presence and absence of standard efflux pump inhibitors. The minimum inhibitory concentration values were also compared to those of strains that do not overexpress these efflux pumps. In order to gain some insights about the efflux pump mechanisms of these chalcones, two homology models were created (NorA and MepA) for a docking procedure. In addition, the ADME properties (absorption, distribution, metabolism and excretion) were also evaluated. The tested chalcones promoted synergism of the norfloxacin antibiotic by inhibiting associated efflux pumps. All four tested chalcones appear to bind to the binding sites of the efflux pump models in the same fashion as other chalcones with efflux pump inhibition capabilities. It was also verified that the chalcones 1-4 are well absorbed in the intestine, but with a decrease in their bioavailability, resulting in a low volume of distribution in the blood plasma, in addition to having a mild CNS activity. However, the chalcone 3 and 4 were not toxic due to metabolic activation. Whereas the chalcones 1 and 2 present a mutagenic risk, depending on the oral dose administered. The tested chalcones have not antibacterial activity; however, they are capable of inhibiting efflux pumps for the 1199B and K2068 strains. They promoted synergism of the norfloxacin antibiotic by inhibiting associated efflux pumps, as well as other associated mechanisms.
Asunto(s)
Chalcona , Chalconas , Acetofenonas/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Chalconas/farmacología , Pruebas de Sensibilidad Microbiana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Staphylococcus aureus/metabolismoRESUMEN
With the spread of bacterial resistance against clinically used antibiotics, natural plant-derived products are being studied as new sources of antibacterial molecules. Manilkara zapota is a common plant species in the American continent that is used as a food source. Studies show the M. zapota extract is rich in phenolic substances that can serve as basic molecules for the pharmaceutical industry. An extract from fresh M. zapota leaves was produced and tested to identify the compounds present, as well as its direct antibacterial and clinical antibiotic modulatory activities. To analyze the results, a new statistical methodology based on the Shannon-Wiener index was tested, capable of correcting distortions in heterogeneous environments. The Hydroethanolic Extract of Manilkara zapota leaves (HEMzL) presented a wide variety of phenolic products, as well as tannins, in the UPLC analysis. The extract showed direct antibacterial activity against the standard Staphylococcus aureus strain, however, it either acted antagonistically when associated with the tested antibiotics, or it did not present statistical significance when compared to the control. This demonstrates a need to be cautious when associating natural products with antibiotics for clinical use, as a hindrance to infectious treatments may occur. As for the statistical analysis mechanism tested, this proved to be effective, reducing false negatives at low antibiotic concentrations and false positives at high concentrations in the microdilution plate.
Asunto(s)
Antibacterianos/farmacología , Cromatografía Liquida/métodos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Manilkara/química , Espectrometría de Masas en Tándem/métodos , Animales , Antibacterianos/análisis , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Escherichia coli/fisiología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/prevención & control , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Fenoles/análisis , Fenoles/farmacología , Fitoterapia/métodos , Extractos Vegetales/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/químicaRESUMEN
Mercury is widely found in nature, however, in low concentrations, but anthropological activities have increased its concentration considerably. This causes various environmental hazards and human health. Many substances are capable of reversing the toxicity of mercuric chloride in the environment. The aim of the present study was to determine the chelating effect of vanillin, as well as to evaluate its capacity for cytoprotection in prokaryotic and eukaryotic plant models. Chelating activity was determined from vanillin's ability to reduce iron III ions. To evaluate cytoprotection in a unicellular prokaryotic and eukaryotic model, Escherichia coli and Candida albicans, respectively, were used. And to evaluate the cytoprotective activity in vegetables, lettuce seeds were submitted to different concentrations of mercuric chloride and its association with the sub-allelopathic concentration of vanillin (32 µg/mL). Vanillin has been found to have antioxidant activity as it can reduce iron III ions. The use of vanillin also allows for better growth and development of Lactuca sativa seed root and stem, also allowing better preservation of its biochemical structures. These results are quite important, as environmental contamination by heavy metals has increased dramatically and finding a viable alternative to grow vegetables in contaminated areas is very valid.
Asunto(s)
Benzaldehídos/química , Biodegradación Ambiental , Quelantes/química , Cloruro de Mercurio/toxicidad , Antioxidantes/química , Compuestos Férricos/química , Humanos , Lactuca , Mercurio , Metales Pesados/análisis , Semillas/química , VerdurasRESUMEN
Human activities, especially in industry, have contributed to soil contamination with heavy or toxic metals. The objective of this study was to determine the chelating effect and antioxidant activity of pyrogallol, as well as to evaluate its cytoprotective activity in prokaryotic and eukaryotic models, animal and plant, respectively, against toxic mercury chloride action. Antioxidant activity was determined by DPPH where pyrogallol showed considerable action, chelating even iron ions. For the microbiologic activity assays, microdilution was performed to obtain the minimal inhibitory concentration, minimum bactericidal and minimum fungicide concentration, from which the sub-inhibitory concentrations were determined. The product did not conferred cytoprotection to the tested bacteria and fungi. To evaluate plant cytoprotection, Lactuta sativa seeds were used together with the product at a sub-allelopathic concentration with different HgCl2 concentrations. In this case, the tannin conferred cytoprotection to the plant model, allowing the best growth and development of caulicles and radicles, thus preserving tissues necessary for plant survival. From the results, it is observable that pyrogallol possesses cytoprotective action in the eukaryotic plant model, this action being useful as an alternative which favors the growth of plants in contaminated areas, as the recovering of crop fields or reforestation projects.
Asunto(s)
Lactuca/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Pirogalol/farmacología , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Alelopatía , Antioxidantes/química , Antioxidantes/farmacología , Quelantes/química , Quelantes/farmacología , Germinación/efectos de los fármacos , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Cloruro de Mercurio/química , Pruebas de Sensibilidad Microbiana , Pirogalol/química , Semillas/efectos de los fármacos , Contaminantes del Suelo/toxicidadRESUMEN
The objective of this study was to determine the chemical profile and to evaluate the antibacterial activity of the essential oils of Piper species and modulation of the antibiotic activity, using the microdilution method to determine the minimum inhibitory concentration. The chemical components were characterized by gas chromatography coupled to mass spectrometry, which revealed ß-copaen-4-α-ol (31.38%), spathulenol (25.92%), and germacrene B (21.53%) as major constituents of the essential oils of Piper arboreum, Piper aduncum, and Piper gaudichaudianum, respectively. The essential oils analyzed in this study did not present a clinically relevant activity against standard and multiresistant Escherichia coli. However, in the case of multiresistant Staphylococcus aureus, there was a significant activity, corroborating with reports in the literature, where Gram-positive bacteria are more susceptible to antimicrobial activity. The essential oils modulated the effect of the antibiotics norfloxacin and gentamicin, having on the latter greater modulating effect; however, for erythromycin, no statistically significant effect was observed. In conclusion, the results obtained in this study demonstrated that the essential oils of the analyzed Piper species present an inhibitory effect against S. aureus and modulate antibiotic activity, most of which presents synergistic activity.
Asunto(s)
Antibacterianos/química , Aceites Volátiles/química , Piper/química , Aceites de Plantas/química , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Sesquiterpenos/análisis , Sesquiterpenos de Germacrano/análisis , Staphylococcus aureus/efectos de los fármacosRESUMEN
The use of natural products together with standard antimicrobial drugs has recently received more attention as a strategy to combat infectious diseases caused by multidrug-resistant (MDR) microorganisms. This study aimed to evaluate the capacity of a galactose-binding lectin from Vatairea macrocarpa seeds (VML) to modulate antibiotic activity against standard and MDR Staphylococcus aureus and Escherichia coli bacterial strains. The minimum inhibitory concentration (MIC) obtained for VML against all strains was not clinically relevant (MIC ≥ 1024 µg/mL). However, when VML was combined with the antibacterial drugs gentamicin, norfloxacin and penicillin, a significant increase in antibiotic activity was observed against S. aureus, whereas the combination of VML and norfloxacin presented decreased and, hence, antagonistic antibiotic activity against E. coli. By its inhibition of hemagglutinating activity, gentamicin (MIC = 50 mM) revealed its interaction with the carbohydrate-binding site (CBS) of VML. Using molecular docking, it was found that gentamicin interacts with residues that constitute the CBS of VML with a score of - 120.79 MDS. It is this interaction between the antibiotic and the lectin's CBS that may be responsible for the enhanced activity of gentamicin in S. aureus. Thus, our results suggest that the VML can be an effective modulating agent against S. aureus. This is the first study to report the effect of lectins as modulators of bacterial sensitivity, and as such, the outcome of this study could lay the groundwork for future research involving the use of lectins and conventional antibiotics against such infectious diseases such as community-acquired methicillin-resistant S. aureus (MRSA).
Asunto(s)
Antibacterianos/farmacología , Interacciones Farmacológicas , Fabaceae/química , Galectinas/farmacología , Proteínas de Plantas/farmacología , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Semillas/químicaRESUMEN
With the increase in bacterial resistance to antibiotics, many studies have been directed towards finding new agents with antibacterial activity, such as studies with natural products. These products can have antibacterial activity such as d-limonene as described in the literature. The aim of this study was to evaluate the antibacterial activity of d-limonene, isolated and complexed with ß-cyclodextrin, and to evaluate its potentiating activity of different antibiotic classes. Antibacterial activity was determined by the broth microdilution method, obtaining in this way the Minimal Inhibitory Concentration (MIC), with the antibiotic modulatory activity being obtained using a sub-inhibitory concentration (MIC/8). d-Limonene showed a MIC equal to 256⯵g/mL against standard S. aureus and 512⯵g/mL against resistant P. aeruginosa. In the gentamicin modulatory activity, the isolated d-limonene presented synergism against S. aureus and E. coli bacteria. Thus, d-limonene showed relevant clinical antibacterial activity, for both Gram-positive and Gram-negative bacteria as well as a synergistic effect when associated with gentamicin. These results are promising in the combat against bacterial resistance, however further studies are needed to better elucidate the mechanisms of action.
Asunto(s)
Antibacterianos/farmacología , Limoneno/química , Limoneno/farmacología , beta-Ciclodextrinas/química , Bacterias/efectos de los fármacosRESUMEN
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⯵g/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.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Ácidos Cafeicos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Eritromicina/farmacología , Ácido Gálico/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Norfloxacino/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Ácidos Cafeicos/química , Farmacorresistencia Bacteriana/genética , Eritromicina/química , Etidio/química , Ácido Gálico/química , Genes MDR/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Norfloxacino/química , Unión Proteica , Conformación Proteica en Hélice alfa , Dominios y Motivos de Interacción de Proteínas , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , TermodinámicaRESUMEN
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 valueâ¯≥â¯1024⯵g/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.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Chenopodium ambrosioides/química , Monoterpenos/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Aceites Volátiles/farmacología , Monoterpenos Ciclohexánicos , Farmacorresistencia Bacteriana/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Norfloxacino/farmacología , Aceites Volátiles/química , Hojas de la Planta/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/metabolismoRESUMEN
In the search for new therapeutic agents against neglected diseases, both aqueous and hydroethanolic extracts from Psidium guajava L. and P. brownianum Mart ex DC leaves were investigated regarding their antiparasitic effect and cytotoxic potential. The extracts were tested at three concentrations (250, 500 and 1000⯵g/mL) against Trypanosoma cruzi epimastigote forms (Chagas, 1909), Leishmania braziliensis (Vianna, 1911) and L. infantum promastigotes forms (Nicolle, 1908), as well as against fibroblasts. P. guajava showed no activity against T. cruzi forms, while the hydroethanolic (PBHE), aqueous by decoction (PBAED) and aqueous by infusion (PBAEI) P. browninaum extracts were responsible, respectively, for inhibiting 100, 100 and 92.68% of T. cruzi epimastigote growth at the 1000⯵g/mL concentration. The P. brownianum hydroethanolic extract (PBHE) at the highest concentration caused 58.46% death in L. braziliensis, thus demonstrating moderate activity, however when tested against L. infantum, the PBHE inhibited their growth by 37.16%, revealing its low activity. As for the cytotoxicity assays, the P. brownianum aqueous extract by decoction (PBAED) obtained the highest death percentage when compared to the others, causing 90.85% fibroblast mortality at the 1000⯵g/mL concentration.
Asunto(s)
Antiparasitarios/farmacología , Leishmania braziliensis/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Extractos Vegetales/farmacología , Hojas de la Planta/química , Psidium/química , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , RatonesRESUMEN
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).
Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Eritromicina/farmacología , Staphylococcus aureus/efectos de los fármacos , Taninos/farmacología , Tetraciclina/farmacología , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana/genética , Eritromicina/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fenotipo , Staphylococcus aureus/genética , Relación Estructura-Actividad , Taninos/química , Tetraciclina/químicaRESUMEN
Cyclodextrins (CDs) have been used as important pharmaceutical excipients for improve the physicochemical properties of the drugs of low solubility as the essential oil of Hyptis martiusii. This oil is important therapeutically, but the low solubility and bioavailability compromises your use. Therein, the aim of this study was to obtain and to characterize physico-chemically the samples obtained by physical mixture (PM), paste complexation (PC) and slurry complexation (SC) of the essential oil Hyptis martiusii (EOHM) in ß-CD, and to compare the antibacterial and modulatory-antibiotic activity of products obtained and oil free. The physicochemical characterization was performed by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Karl Fischer titration. Additionally, the antibacterial tests were performed by microdilution technique. Thus, it was observed that the PM method showed low complexing capacity, unlike PC and SC in which it was observed the formation of inclusion complexes. In addition, the second stage of the TG/DTG curves showed that SC was the best method inclusion with mass loss of 6.9% over the PC that was 6.0%. The XRD results corroborate with the results above suggesting the formation of new solid phase and the SEM photomicrographs showed the porous surface of the samples PC and SC. The essential oil alone demonstrated an antibacterial and modulatory effect against the S. aureus and the Gram negative strain, respectively. However, the ß-CD and the inclusion complex did not demonstrate any biological activity in the performed antibacterial assays.
Asunto(s)
Antibacterianos/química , Hyptis/química , Aceites Volátiles/química , beta-Ciclodextrinas/química , Antibacterianos/farmacología , Rastreo Diferencial de Calorimetría/métodos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Composición de Medicamentos/métodos , Bacterias Gramnegativas/efectos de los fármacos , Aceites Volátiles/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Staphylococcus aureus/efectos de los fármacos , Difracción de Rayos X/métodos , beta-Ciclodextrinas/farmacologíaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Chenopodium ambrosioides/química , Monoterpenos/farmacología , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Staphylococcus aureus/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Monoterpenos Ciclohexánicos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismoRESUMEN
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.
RESUMEN
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).