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Objective: To evaluate the inhibitory activity of ferulic acid and four of its esterified derivatives (methyl, ethyl, propyl, and butyl) against resistance mechanisms in Staphylococcus aureus strains. Methods: Ferulic acid derivatives were obtained by esterification with methanol, ethanol, propanol, and butanol, and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and norfloxacin were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs of norfloxacin and ethidium bromide. Molecular docking was also carried out using the Schrodinger Suite 2015 molecular modeling software. A three-dimensional model of NorA efflux pump was generated using I-TASSER. The best scoring model was used as a receptor for ligand-receptor docking. Results: The methyl and butyl ester derivatives did not demonstrate significant antimicrobial activity. However, a significant synergic effect was evidenced when norfloxacin was combined with the ethyl and propyl esterified derivatives. The docking study demonstrated favorable energy of interaction between ferulate derivatives and NorA, and amino acid residues TYR57, TYR58, and LEU255 were present commonly in stabilizing all complexes. The PCA analysis corroborated the docking hypothesis that the lipophilic character and hydrogen bond interactions were the most relevant characteristics involved with NorA inhibitors. The pharmacokinetic parameters of ferulic acid derivatives showed good ADMET properties, demonstrating that they can be easily absorbed and have no effect or inhibit the cytochrome P450 enzyme complex, revealing their potential as drug candidates. Conclusions: This study provides strong evidence that the molecular basis for this activity is potentially due to the NorA efflux pump.

This study aimed to evaluate the intrinsic antibacterial activity and antibiotic-enhancing effect of an arylamino methylene derivative (MAD) in association with fluoroquinolones. The antibacterial activity against multiresistant Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli was analyzed by determining the minimum inhibitory concentration (MIC) using the broth micro dilution method. A reduction in the MIC of the fluoroquinolones against strains treated simultaneously with the MAD was interpreted as an enhanced antibiotic activity. While the MAD exhibited no clinically effective action (MIC ≥ 1.024 µg/mL), it was found to significantly potentiate the activity of norfloxacin, ofloxacin and lomefloxacin against all the strains, which may be related to structural similarities between the MAD and quinolones. Our findings suggest that Meldrum’s acid arylamino derivatives may represent promising molecules in the elaboration of new drugs to reverse resistance to fluoroquinolones.

Bacterial resistance to multiple drugs has recently emerged as a serious health problem. Concomitantly, the characterization of new substances with potential antimicrobial activity has been less frequent in the drug development industry. The overexpression of genes encoding efflux pumps that expel antimicrobial drugs from the intracellular environment, lowering these to subinhibitory concentrations, are among the resistance mechanisms predisposing microorganisms to high drug resistance.Ferulic acid derivatives were obtained by esterification and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and antibiotics were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs.Propylferulate was seen to reduce the minimum inhibitory concentration (MIC) of both the control substance ethidium bromide and the tested antibiotic, indicating that this compound is promising for the use of efflux pump inhibition of IS-58 strains.This study provides strong evidence that the molecular basis for this activity is potentially due to the MsrA and TetK efflux pumps. However, further investigations are necessary to prove this hypothesis and elucidate the potentiating mechanism of the modulatory effect.

Liposomes, in addition to providing greater efficacy to antibiotics, decrease toxicity and increase selectivity. This work has as main objectives the sensitization of the need to solve bacterial resistance to antibiotics, addressing the potential of antibiotics carried by liposome. In the preparation of the liposomes, the lipids dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylserine (DPPS), and cholesterol (COL) with 99% purity were used. The Staphylococcus aureus strains used were SA-1199B, which expresses the NorA gene encoding the NorA efflux protein, which expels hydrophilic fluoroquinolones and other drugs intercalating DNA dyes, and the wild strain SA-1199. The liposomes associated with antibiotics in the wild type of strain SA-1199 and the carrier strain of pump 1199B, had a better representation of growth inhibition than the wild type strain SA-1199. Given the potential for inhibition of efflux pump seen in the results, we highlight the creation of new drugs or alteration of existing drugs. They are not recognized by the efflux pumps and removed from the target cell.

Antimicrobial resistance and the consequent inefficiency of antibiotics are the main problems faced by medicine. In view of this, numerous researches have been aimed at looking for new agents with antibacterial activity, among them natural products. Thus, this study aims to evaluate the antioxidant activity of aqueous and hydroalcoholic extracts of the leaves and roots of Spondias tuberosa by Thin Layer Chromatography (TLC), as well as to verify the antibacterial action of the extracts alone and in combination with commercial antibiotics to evaluate its potential in action of change of antibiotics. The extracts showed polar and nonpolar phenolic substances with antioxidant action. The Minimum Inhibitory Concentration (MIC) of the hydroalcoholic extracts of the leaves and roots was 1,024 μg/mL compared to the Staphylococcus aureus 25923 strain, whereas with the other strains, the products showed an MIC ≥ 2,048 µg/mL. The effect of combining extracts with amikacin, ampicillin and norfloxacin against the multidrug-resistant bacteria Escherichia coli 06, Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 resulted in synergistic effects with aminoglycoside alone, achieving up to 75 % reduction in the MIC of the antibiotic. In view of the results obtained, it can be concluded that the extracts of S. tuberosa presented polar and nonpolar phenolic substances, in the antibacterial activity it can positively modify the effect of the aminoglycoside antibiotic against multi-resistant bacteria, but future studies are necessary to discover the mechanism of action of such an effect. La resistencia a los antimicrobianos y la consiguiente ineficacia de los antibióticos son los principales problemas a los que se enfrenta la medicina. Ante esto, numerosas investigaciones se han dirigido a buscar nuevos agentes con actividad antibacteriana, entre ellos productos naturales. Así, este estudio tiene como objetivo evaluar la actividad antioxidante de extractos acuosos e hidroalcohólicos de las hojas y raíces de Spondias tuberosa mediante Cromatografía de Capa Fina (CCF), así como verificar la acción antibacteriana de los extractos solos y en combinación con antibióticos comerciales para evaluar su potencial en la acción del cambio de antibióticos. Los extractos mostraron sustancias fenólicas polares y apolares con acción antioxidante. La Concentración Mínima Inhibitoria (CMI) de los extractos hidroalcohólicos de hojas y raíces fue de 1.024 μg / mL en comparación con la cepa Staphylococcus aureus 25923, mientras que con las otras cepas, los productos mostraron una CMI ≥ 2.048 µg / mL. El efecto de combinar extractos con amikacina, ampicilina y norfloxacina contra la bacteria multirresistente Escherichia coli 06, Staphylococcus aureus 10 y Pseudomonas aeruginosa 24 resultó en efectos sinérgicos con el aminoglucósido solo, logrando reducción de hasta un 75 % en la CMI del antibiótico. A la vista de los resultados obtenido, se puede concluir que los extractos de S. tuberosa presentó sustancias fenólicas polares y apolares, en el actividad antibacteriana puede modificar positivamente el efecto del antibiótico aminoglucósido contra bacterias multirresistentes, pero el futuro son necesarios estudios para descubrir el mecanismo de acción de tal efecto. A resistência antimicrobiana e a consequente ineficiência de antibióticos são os principais problemas enfrentados pela medicina. Diante disto, inúmeras pesquisas têm sido destinadas a procurar novos agentes com atividade antibacteriana, dentre eles os produtos naturais. Dessa forma, esse estudo tem como objetivo avaliar a atividade antioxidante dos extratos aquosos e hidroalcoólicos das folhas e raízes de S. tuberosa Arruda (umbu) por Cromatografia em Camada Delgada (CCD), bem como verificar a ação antibacteriana dos extratos isoladamente e em combinação com antibióticos comerciais para avaliar seu potencial na ação de modificação de antibióticos. Os extratos apresentaram substâncias fenólicas polares e apolares com ação antioxidante. A Concentração Inibitória Mínima (CIM) dos extratos hidroalcoólicos das folhas e raízes foi 1024 μg/mL frente a cepa Staphylococcus aureus 25923, já com as demais cepas os produtos demonstraram uma CIM ≥ 2.048 µg/mL. O efeito da combinação dos extratos com amicacina, ampicilina e norfloxacina frente às bactérias multirresistentes Escherichia coli 06, Staphylococcus aureus 10 e Pseudomonas aeruginosa 24 resultou em efeitos sinérgicos apenas com o aminoglicosídeo, alcançando até 75 % de redução da CIM do antibiótico. Diante dos resultados obtidos, pode-se concluir que os extratos de S. tuberosa apresentaram substâncias fenólicas polares e apolares, na atividade antibacteriana pode modificar positivamente o efeito do antibiótico aminoglicosídeo contra bactérias multirresistentes, mas estudos futuros é preciso para descobrir o mecanismo de ação de tal efeito.

Chalcones and their derivatives are substances of great interest for medicinal chemistry due to their antibacterial activities. As the bacterial resistance to clinically available antibiotics has become a worldwide public health problem, it is essential to search for compounds capable of reverting the bacterial resistance. As a possibility, the chalcone class could be an interesting answer to this problem. The chalcones (2E)-1-(4'-aminophenyl)-3-(phenyl)‑prop-2-en-1-one (APCHAL), and (2E)-1-(4'-aminophenyl)-3-(4-chlorophenyl)‑prop-2-en-1-one (ACLOPHENYL) were synthesized by the Claisen-Schmidt condensation and characterized by 1H and 13C nuclear magnetic resonance (NMR), Fourier-transform infrared (FT-IR), and mass spectrometry (MS), In addition, microbiological tests were performed to investigate the antibacterial activity, modulatory potential, and efflux pump inhibition against Staphylococcus aureus (S. aureus) multi-resistant strains. Regarding the S. aureus Gram-positive model, the APCHAL presented synergism with gentamicin and antagonism with penicillin. APCHAL reduced the Minimum inhibitory concentration (MIC) of gentamicin by almost 70%. When comparing the effects of the antibiotic modifying activity of ACLOPHENYL and APCHAL, a loss of synergism is noted with gentamicin due to the addition of a chlorine to the substance structure. For Escherichia coli (E. coli) a total lack of effect, synergistic or antagonistic, was observed between ACLOPHENYL and the antibiotics. In the evaluation of inhibition of the efflux pump, both chalcones presented a synergistic effect with norfloxacin and ciprofloxacin against S. aureus, although the effect is much less pronounced with ACLOPHENYL. The effect of APCHAL is particularly notable against the K2068 (MepA overexpresser) strain, with synergistic effects with both ciprofloxacin and ethidium bromide. The docking results also show that both compounds bind to roughly the same region of the binding site of 1199B (NorA overexpresser), and that this region overlaps with the preferred binding region of norfloxacin. The APCHAL chalcone may contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant S. aureus.

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.

Essential oils are secondary metabolites with immense pharmacological potential.These substances are abundantly produced by plants of the family Asteraceae, such as Baccharis coridifolia. Previous studies have demonstrated that this species has pharmacological properties that make it a promising source of new antibacterial agents. Therefore, the present study aimed to evaluate the antibacterial and antibiotic-modulating activity of Baccharis coridifolia essential oil against multidrug-resistant (MDR) strains. The phytochemical analysis was carried out by gas chromatography coupled to Mass Spectroscopy (GC/MS), and realized the Minimum Inhibitory Concentation (MIC) and antibiotic-modulation from the microdilution method in 96-well plates. It was revealed the presence of germacrene D (23.7%), bicyclogermacrene (17.1%), and (E)-caryophyllene (8.4%) as major components. The minimum inhibitory concentration of essential oil against strains of Pseudomonas aeruginosa (512 μg/mL) and Staphylococcus aureus (128 μg/mL) demonstrated clinically relevant antibacterial activity. In addition, the combination of subinhibitory doses of the oil with conventional antibiotics showed synergism, indicating potentiation of the antibacterial effect. In conclusion, the essential oil of Baccharis coridifolia (EOBc) presented antibacterial and antibiotic-modulating activities that place this species as a source of molecules useful in the fight against bacterial resistance.

This study is a pioneer in reporting the antibacterial properties of the species Croton ceanothifolius Baill. The genus Croton belongs to the family Euphorbiaceae composed of numerous species with documented biological activities. However, the pharmacological properties of C. ceanothifolius remain poorly understood. The leaves of this plant were submitted to hydrodistillation for essential oil (CcEO) extraction and the phytochemical characterization of the oil was performed by GC/MS. The minimum inhibitory concentration of the CcEO was determined for the evaluation of antibacterial activity against multiresistant strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The antibiotic-modulating activity of the oil, in combination with antibiotics, was also evaluated. The combination of the CcEO with penicillin, norfloxacin, and gentamicin presented a synergistic effect. This effect was more significant for the association with antibiotics of the quinolone and aminoglycoside classes against Escherichia coli. The association of oil with gentamicin showed better results with regard to the Gram-positive strain. The association of the oil with norfloxacin against P. aeruginosa also showed synergism, but the association with penicillin did not change the effect of this antibiotic. Thus, it is concluded that C. ceanothifolius essential oil selectively potentiates the action of antibiotics against multiresistant strains.

Concerns regarding environmental contamination by heavy metals extends worldwide with some studies showing promising alternatives for soil recovery using plants. This research aimed to evaluate the ability of rutin flavonoid to reduce the toxicity of mercury dichloride (HgCl2) in microbiological and vegetable models, by antioxidant tests (DPPH) and chelating assays with Ferro (Fe II) and Ferro (Fe III). The reduction in toxicity was then assessed using microbial models. The cytoprotective potential was evaluated in Lactuca sativa (lettuce) using the products in suballelopathic concentrations of HgCl2. Rutin flavonoid did not reduce the toxicity of HgCl2 in microbiological models, but it improved the development of roots and stems in lettuce seedlings, probably due to the coordination of mercury with the rutin molecule, reducing the toxicity of the metal. The interaction of rutin with mercury chloride was evidenced by vibrational spectroscopy. Although HgCl2 causes cytotoxicity in several plant species, its complex with rutin can mitigate these effects. This is the first report on the cytoprotective activity of rutin flavonoid in a prokaryotic and eukaryotic model against the toxic action of HgCl2.

Curcumin, along with its derivatives, form a large class of natural and synthetic compounds with notable biological activity. However, their highly reactive β-diketone moiety renders this type of compounds unstable at pH above 6.5. The substitution of this group for a mono-carbonyl solves this problem, while improving antibacterial and anti-inflammatory activities. A thiophene curcuminoid, (1E,4E)-1,5-Di(thiophen-2-yl)penta-1,4-dien-3-one (DB Thiophene), has been synthesised and its molecular and spectroscopic characterization is reported, as well as a complete vibrational assignment. An efflux pump inhibition assay determined that DB Thiophene exhibits a remarkable NorA and MepA efflux pump inhibition activity. Molecular docking studies were carried out in order to understand this inhibition mechanism.