A structure–activity relationship study of flavonoids as inhibitors of E. coli by membrane interaction effect

Flavonoids exhibit a broad range of biological activities including antibacterial activity. However, the mechanism of their antibacterial activity has not been fully investigated. The antibacterial activity and membrane interaction of 11 flavonoids (including 2 polymethoxyflavones and 4 isoflavonoids) against Escherichia coli were examined in this study. The antibacterial capacity was determined as flavonoids > polymethoxyflavones > isoflavonoids. Using fluorescence, it was observed that the 5 flavonoids rigidified the liposomal membrane, while the polymethoxyflavones and isoflavonoids increased membrane fluidity. There was a significant positive correlation between antibacterial capacity and membrane rigidification effect of the flavonoids. A quantitative structure–activity relationship (QSAR) study demonstrated that the activity of the flavonoid compounds can be related to molecular hydrophobicity (CLogP) and charges on C atom at position3 (C3). The QSAR model could be used to predict the antibacterial activity of flavonoids which could lead to natural compounds having important use in food and medical industry.     

The influence of halogen substituents on the biological properties of sulfur-containing flavonoids

A series of halogen-substituted tricyclic flavonoids containing a 1,3-dithiol-2-ylium moiety has been synthesized from the corresponding 3-dithiocarbamic flavanones. The influence of halogen substituents on the antibacterial properties of the tricyclic flavonoids has been investigated against Staphylococcus aureus and Escherichia coli. On going from fluorine to iodine, these compounds exhibit good to excellent inhibitory properties against both Gram-positive and Gram-negative pathogens. These results suggest that size is the main factor for the change in potency rather than polarity/electronics.     

Synergistic activity and mode of action of flavonoids isolated from smaller galangal and amoxicillin combinations against amoxicillin-resistant Escherichia coli

Aim: The smaller galangal is extracted, purified and identified the bioactive compounds. The purpose of this research was to investigate whether these isolated compounds have antibacterial and synergistic activity against amoxicillin‐resistant Escherichia coli (AREC) when used singly and in combination with amoxicillin. The primarily mode of action is also studied. Method and Results: The galangin, kaempferide and kaempferide‐3‐O‐β‐d ‐glucoside were isolated. The minimum inhibitory concentrations(MIC) of amoxicillin and these flavonoids against AREC were between 500 and >1000 μg ml^?1. Synergistic activity was observed on combining amoxicillin with these flavonoids. The combinations of amoxicillin and these flavonoids exhibited a synergistic effect, reducing AREC cell numbers. Electron microscopy showed that these combinations damaged the ultrastructure of AREC cells. The results indicated that these combinations altered outer membrane permeability but not affecting cytoplasmic membrane. Enzyme assays showed that these flavonoids had an inhibitory activity against penicillinase. Conclusion: These results indicated that these flavonoids have the potential to reverse bacterial resistance to amoxicillin in AREC and may operate via three mechanisms: inhibition of peptidoglycan and ribosome synthesis, alteration of outer membrane permeability, and interaction with β‐lactamases. Significance and Impact of the Study: These findings offer the potential to develop a new generation of phytopharmaceuticals to treat AREC.     

Three flavonoids targeting the beta-hydroxyacyl-acyl carrier protein dehydratase from Helicobacter pylori: crystal structure characterization with enzymatic inhibition assay

Flavonoids are the major functional components of many herbal and insect preparations and demonstrate varied pharmacological functions including antibacterial activity. Here by enzymatic assay and crystal structure analysis, we studied the inhibition of three flavonoids (quercetin, apigenin, and (S)-sakuranetin) against the beta-hydroxyacyl-acyl carrier protein dehydratase from Helicobacter pylori (HpFabZ). These three flavonoids are all competitive inhibitors against HpFabZ by either binding to the entrance of substrate tunnel B (binding model A) or plugging into the tunnel C near the catalytic residues (binding model B) mainly by hydrophobic interaction and hydrogen-bond pattern. Surrounded by hydrophobic residues of HpFabZ at both positions of models A and B, the methoxy group at C-7 of (S)-sakuranetin seems to play an important role for the inhibitor's binding to HpFabZ, partly responsible for the higher inhibitory activity of (S)-sakuranetin than those of quercetin and apigenin against HpFabZ (IC(50) in microM: (S)-sakuranetin, 2.0 +/- 0.1; quercetin: 39.3 +/- 2.7; apigenin, 11.0 +/- 2.5). Our work is expected to supply useful information for understanding the potential antibacterial mechanism of flavonoids.     

Antibacterial activity and mode of action of plant flavonoids against Proteus vulgaris and Staphylococcus aureus

(−)-Epigallocatechin, an antibiotic found in Elaeagnus glabra, and 28 other related plant flavonoids were tested for their antibacterial activity against Proteus vulgaris and Staphylococcus aureus. A free 3′,4′,5′-trihydroxy B-ring and a free 3-OH were necessary for antibacterial activity. DNA synthesis was predominantly inhibited by the active flavonoids in P. vulgaris, whereas RNA synthesis was inhibited in S. aureus.     

Isolation of antimicrobial compounds from guava (Psidium guajava L.) and their structural elucidation

Four antibacterial compounds were isolated from leaves of guava (Psidium guajava L.), and the structures of these compounds were established on the basis of chemical and spectroscopic evidence. Two new flavonoid glycosides, morin-3-O-alpha-L-lyxopyranoside and morin-3-O-alpha-L-arabopyranoside, and two known flavonoids, guaijavarin and quercetin, were identified. The minimum inhibition concentration of morin-3-O-alpha-L-lyxopyranoside and morin-3-O-alpha-L-arabopyranoside was 200 microg/ml for each against Salmonella enteritidis, and 250 microg/ml and 300 microg/ml against Bacillus cereus, respectively.     

黄酮类化合物抑制微生物活性及其作用机制

本文综述了黄酮类化合物抑制细菌、病毒和真菌的活性及可能的作用机制,黄酮类化合物结构与抑菌活性之间的关系。结果表明,黄酮类化合物主要通过抑制细菌DNA旋转酶,抑制细菌细胞质膜的功能,抑制细菌能量代谢等方面发挥抑菌功效。指出黄酮类化合物是今后抗病源微生物药物开发新的研究方向。     

Antimicrobial evaluation of coumarins and flavonoids from the stems of Daphne gnidium L.

The antimicrobial activity of stems methanol extract from Daphne gnidium L. collected from Sardinia (Italy) was evaluated against 6 strains of standard and clinical isolated gram (+/-) bacteria. The antimicrobial effect on two strains of fungi was also tested. The extract in toto exhibited antibacterial activity against Bacillus lentus and Escherichia coli, but was inactive against fungi. Four coumarins (daphnetin, daphnin, acetylumbelliferone, daphnoretin) and seven flavonoids (luteolin, orientin, isoorientin, apigenin-7-O-glucoside, genkwanin, 5-O-beta-D-primeverosyl genkwanine, 2,5,7,4'-tetrahydroxyisoflavanol) present in the plant extract were also investigated against the same strains of bacteria and fungi assayed for the crude extract. The most active compounds were daphnetin, genkwanin, and 2,5,7,4'-tetrahydroxyisoflavanol.     

Prenylated flavonoids from Desmodium caudatum and evaluation of their anti-MRSA activity

Seven prenylated flavonoids and a prenylated chromanochroman derivative, together with eight known flavonoids, were isolated from roots of Desmodium caudatum. The 15 structures were elucidated by extensive spectroscopic analyses. The antibacterial activity of many of other compounds was evaluated against methicillin-resistant Staphylococcus aureus (MRSA: COL and 5) by a disc diffusion method, and the minimum inhibitory concentrations (MICs) to MRSA were determined.     

Activities of Wogonin Analogs and Other Flavones against Flavobacterium columnare

In our on‐going pursuit to discover natural products and natural product‐based compounds to control the bacterial species Flavobacterium columnare, which causes columnaris disease in channel catfish (Ictalurus punctatus), we synthesized flavone and chalcone analogs, and evaluated these compounds, along with flavonoids from natural sources, for their antibacterial activities against two isolates of F. columnare (ALM‐00‐173 and BioMed) using a rapid bioassay. The flavonoids chrysin ( 1a ), 5,7‐dihydroxy‐4′‐methoxyflavone ( 11 ), isorhamnetin ( 26 ), luteolin ( 27 ), and biochanin A ( 29 ), and chalcone derivative 8b showed strong antibacterial activities against F. columnare ALM‐00‐173 based on minimum inhibition concentration (MIC) results. Flavonoids 1a, 8, 11, 13 (5,4′‐dihydroxy‐7‐methoxyflavone), 26 , and 29 exhibited strong antibacterial activities against F. columnare BioMed based upon MIC results. The 24‐h 50% inhibition concentration (IC₅₀) results revealed that 27 and 29 were the most active compounds against F. columnare ALM‐00‐173 (IC₅₀ of 7.5 and 8.5 mg/l, resp.), while 26 and 29 were the most toxic compound against F. columnare BioMed (IC₅₀ of 9.2 and 3.5 mg/l, resp.). These IC₅₀ results were lower than those obtained for wogonin against F. columnare ALM‐00‐173 and F. columnare BioMed (28.4 and 5.4 mg/l, resp.). However, based on MIC results, none of the compounds evaluated in this study were as active as wogonin (MIC 0.3 mg/l for each F. columnare isolate). Further modification of the wogonin structure to enhance antibacterial is of interest.     

Antimicrobial activity and synergism of some substituted flavonoids

Natural and synthetic substituted chalcones, flavones and flavanones were tested for antibacterial activity. In order to determine synergism, new combinations of substituted flavonoids against Staphylococcus aureus, Escherichia coli and Enterobacter aerogenes were assayed. The results allow us to establish relationships between antimicrobial effect of the compounds and membrane structures of these microorganisms. When flavonoid combinations were employed a stronger effect was found against E. coli than against S. aureus. This fact is due to the existence of porins in the outer membrane of G(-)-bacteria. The compound that acts as enhancer acts by blocking the charges of amino acids in the porins and thus facilitates the passage of the other compound by diffusion into the bacterial cell.     

Evaluation of the medicinal potentials of the methanol extracts of the leaves and stems of Halleria lucida

The medicinal potentials of the methanol extracts of the leaves and stems of Halleria lucida (Scrophulariaceae) were evaluated by assessing their antibacterial and antioxidant properties in vitro using standard procedures. The antioxidant activities of methanol extract of the leaves as determined by the ABTS, DPPH, proanthocyanidins and total flavonoids were higher than that of the stem. On the other hand, the total phenols, the flavonoids and the FRAP contents of the stem were higher than that of the leaves. The extracts however showed poor activity against both Gram-positive and Gram-negative bacteria. The methanol extract of the stem showed activities against Bacillus cereus and Staphylococcus epidermidis at MIC of 1.0 mg/ml. The methanol extract of the leaves did not show activity against any of the organisms used in this study. This study has to some extent validated the medicinal potential of the leaves and stems of H. lucida.     

In vitro antimicrobial activity of six medicinal plants traditionally used for the treatment of dysentery and diarrhoea in Democratic Republic of Congo (DRC).

Twenty-four crude extracts derived from six medicinal plants highly valued as antidiarrhoeal agents in Congolese folk medicine were screened for antimicrobial activity against several enteric pathogens. The results of this study indicated that the methanolic and aqueous extracts derived from three of them (Roureopsis obliquifoliolata, Epinetrum villosum and Cissus rubiginosa) possessed prominent antibacterial activity, therefore supporting the ethnomedical uses of these species. In addition, phytochemical analysis of these medicinal plants showed that 1/6 plant sample contained alkaloids, 6/6 triterpenes and/or sterols, 4/6 flavonoids, 3/6 tannins and 5/6 saponins. Anthraquinones were not detected in any of these plants.     

一株酸枣内生菌的鉴定及其抗菌活性物质的初步分离

为了从酸枣中筛选出内生菌并分析其代谢产物中的活性成分,用于开发和生产药物,该研究通过组织块分离法和划线分离法,从陕北野生酸枣植株体内分离得到内生菌,采用平板对峙法测定其对7株供试指示菌的抗菌活性,以心神宁片提取液为对照,对各拮抗菌株的发酵液进行薄层层析和高效液相色谱分析。结果表明:从野生酸枣中共分离得到121株内生菌,其中内生细菌49株,内生放线菌6株,内生真菌66株;通过抗菌试验,发现54株内生菌(细菌33株,真菌21株)对1～7种指示菌具有抗菌活性,占分离菌株总菌数的44.63%,其中A-04、A-05、B-03、C-03、C-06和D-04共6株菌株的抗菌谱较广,对7种供试指示菌均具有抑菌活性;薄层层析检测结果显示菌株B-03发酵产物在R_f值为0.46处有与酸枣提取液层析带迁移率相同的显色带,液相色谱分析结果显示其属于黄酮类物质;通过16S rRNA基因序列分析结果显示菌株B-03与Bacillus axarquiensis的相似性为99%。菌株B-03能发酵产生黄酮类或产生与黄酮类类似的化合物,表明酸枣内生菌具有合成黄酮类药物的潜力。     

Formation of novel flavonoids in apple (Malusxdomestica) treated with the 2-oxoglutarate-dependent dioxygenase inhibitor prohexadione-Ca

Novel flavonoids were formed in young leaves of apple (Malusxdomestica) after treatment with the dioxygenase inhibitor prohexadione-Ca, which is known to reduce the incidence and severity of fire blight caused by Erwinia amylovora and other plant diseases. The compounds were isolated and identified as luteoliflavan, luteoliflavan 5-glucoside, eriodictyol 7-glucoside and 6"-O-trans-p-coumaroyleriodictyol 3'-glucoside. These flavonoids represent a novel biosynthetic pathway in apple leading to the formation of 3-deoxyflavans. Concomitantly, the content of regularly occurring phenylpropanoids is also influenced by prohexadione-Ca with increasing amounts of hydroxycinnamic acids and decreasing flavan-3-ols and flavonols. The altered flavonoid metabolism may be related to the lowered pathogen incidence though the isolated novel flavonoids do not exhibit antibacterial activity.     

黄酮化合物对耐药性鲍曼不动杆菌抑菌作用研究

为探索中药黄酮化合物对耐药性鲍曼不动杆菌的抑菌效果。研究通过微量肉汤稀释法,考察40种中药及天然来源的黄酮化合物对三株耐药性鲍曼不动杆菌菌株的体外抑菌作用,测试其最低抑菌浓度与最低杀菌浓度;采用结晶紫染色法进一步测定目标化合物对鲍曼不动杆菌生物被膜形成的能力;探索黄酮联合头孢哌酮/舒巴坦对鲍曼不动杆菌的抑菌效果。研究表明,黄酮单体对于鲍曼不动杆菌具有不同程度的体外抑菌作用。其中部分具有轻微作用,其最小抑菌浓度仅为0.5 mg/mL;黄芩素和汉黄芩苷具有显著的抑菌作用,其最小抑菌浓度分别为0.062 5和0.125 mg/mL;同时,黄芩素对鲍曼不动杆菌生物被膜形成具有明显的抑制作用。此外,黄芩素和头孢哌酮/舒巴坦联合作用于耐药鲍曼不动杆菌与单用黄芩素或头孢哌酮/舒巴坦比较,浓度有所降低。综上,黄芩素对耐药性鲍曼不动杆菌有较好的体外抑菌效果,这为治疗耐药性鲍曼不动杆菌引发的感染的治疗提供新思路和方向。     

Antiproliferative activity of flavonoids on several cancer cell lines.

Twenty-seven Citrus flavonoids were examined for their antiproliferative activities against several tumor and normal human cell lines. As a result, 7 flavonoids were judged to be active against the tumor cell lines, while they had weak antiproliferative activity against the normal human cell lines. The rank order of potency was luteolin, natsudaidain, quercetin, tangeretin, eriodictyol, nobiletin, and 3,3',4',5,6,7,8-heptamethoxyflavone. The structure-activity relationship established from comparison among these flavones and flavanones showed that the ortho-catechol moiety in ring B and a C2-C3 double bond were important for the antiproliferative activity. As to polymethoxylated flavones, C-3 hydroxyl and C-8 methoxyl groups were essential for high activity.     

Antibacterial activity of coumarins

The antibacterial activity of coumarin per se and other 45 coumarin derivatives was tested against strains of Bacillus cereus MIP 96016, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 25923. The inhibitory effects of coumarins were affected by their substitution patterns. Osthenol (44) showed the most effective antibacterial activity against Gram-positive bacteria with MIC values ranging between 125 and 62.5 microg/ml. These results suggested that the prenyl chain of 44 at position 8 and the presence of OH at position 7 of the benzenic ring are required for the antibacterial activity against these strains.     

Synthesis of (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives as antifungal, antibacterial, and anticancer agents

A series of (1,4)-naphthoquinono [3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives 2-7 were synthesized and evaluated for antifungal, antibacterial, and anticancer activities. The structure-activity relationship of these compounds was studied and the results show that the compound 2b exhibited in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, and also possessed antibacterial profile against Klebsiella pneumoniae and Escherichia coli whereas 1c showed anticancer activity against Walker 256 Carcinosarcoma in rats.     

Structure elucidation of anti-methicillin resistant Staphylococcus aureus (MRSA) flavonoids from balsam poplar buds

There is nowadays an urgent need for developing novel generations of antibiotic agents due to the increased resistance of pathogenic bacteria. As a rich reservoir of structurally diverse compounds, plant species hold promise in this regard. Within this framework, we isolated a unique series of antibacterial flavonoids, named balsacones N–U, featuring multiple cinnamyl chains on the flavan skeleton. The structures of these compounds, isolated as racemates, were determined using extensive 1D and 2D NMR analysis in tandem with HRMS. Balsacones N–U along with previously isolated balsacones A–M were evaluated for their antibacterial activity against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA). Several of the tested balsacones were potent anti-MRSA agents showing MIC values in the low micromolar range. Structure–activity relationships study highlighted some important parameters involved in the antibacterial activity of balsacones such as the presence of cinnamyl and cinnamoyl chains at the C-3 and C-8 positions of the flavan skeleton, respectively. These results suggest that balsacones could represent a potential novel class of naturally occurring anti-MRSA agents.