Flavonoid-Related Modulators of Multidrug Resistance:  Synthesis, Pharmacological Activity, and Structure−Activity Relationships

Ferté, Jacques; Kühnel, Jean-Marc; Chapuis, Geneviève; Rolland, Y.; Lewin, Guy; Schwaller, Marc Antoine

doi:10.1021/jm981064b

Cited by 107 publications

(63 citation statements)

References 32 publications

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“…Any prospective microbial MDR inhibitor to be used in medicine should be devoid of activity against P-glycoprotein MDR that is responsible for multidrug resistance of tumors and plays a role in toxin extrusion from normal cells (18). Interestingly, flavonoids with alkylated 7-O groups were active against Pglycoprotein, whereas 7-OH forms were completely inactive, apparently because of acidic properties of this group (19). The 7-OH containing 5Ј-MHC is likely to be a specific microbial MDR inhibitor.…”

Section: Resultsmentioning

confidence: 99%

Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor

Stermitz

Lorenz

Tawara

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

651

461

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Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5-methoxyhydnocarpin (5-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.multidrug resistance ͉ efflux inhibitor B acteria have evolved numerous defenses against antimicrobial agents, and drug-resistant pathogens are on the rise (1). A general and effective defense is conferred by ubiquitous multidrug resistance pumps (MDRs), membrane translocases that extrude structurally unrelated toxins from the cell (2-5). Preferred substrates of most MDRs are synthetic hydrophobic cations such as quaternary ammonium antiseptics (6, 7). We have identified a group of cationic berberine alkaloids as natural substrates of MDR pumps (6). We suggested that berberine alkaloids represent a possibly larger group of cationic toxins that fueled the evolution of MDRs (7). Considering that microbial MDRs can render berberine alkaloids essentially ineffective, we reasoned that plants would benefit from making an MDR inhibitor. Here we show that Berberis fremontii, a berberine producer (8) used in Native American traditional medicine (9, 10), synthesizes a potent MDR inhibitor. Structural determination identified the substance as 5Ј-methoxyhydnocarpin (5Ј-MHC). Efflux of berberine from pathogenic Staphylococcus aureus expressing the NorA MDR pump that confers resistance to quinolones and antiseptics (6,11,12) was inhibited completely by 5Ј-MHC. This is a clear example of synergy between components of a medicinal plant described at a molecular level. Materials and MethodsCell Culturing and Susceptibility Testing. S. aureus 4222 parent strain and the norA mutant KLE 820 (6) were cultured in Mueller-Hinton (MH) broth. Cells (10 5 ͞ml) were inoculated into MH broth and dispensed at 0.2 ml͞well in microtiter plates. All tests were done in triplicate by following National Center for Clinical Laboratory Standards recommendations. Briefly, minimal inhibitory concentrations (MIC) were determined by serial 2-fold dilution of test compounds. MIC was defined as a concentr...

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Section: Resultsmentioning

confidence: 99%

Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor

Stermitz

Lorenz

Tawara

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

651

461

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“…A tool capable of quantitatively evaluating these opposite responses made it possible to test the hypothesis that MDR-like ABC transporters, and the auxin transport processes they participate in, are regulated by flavonoid compounds. The flavonoid compound quercetin is known to affect auxin efflux and has been reported to bind to mammalian (Ferté et al, 1999) MDR transporters. PGP1-mediated auxin efflux in heterologous systems is also sensitive to physiologically relevant amounts of quercetin (Geisler et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Separating the Roles of Acropetal and Basipetal Auxin Transport on Gravitropism with Mutations in Two Arabidopsis Multidrug Resistance-Like ABC Transporter Genes

et al. 2007

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Two Arabidopsis thaliana ABC transporter genes linked to auxin transport by various previous results were studied in a reverse-genetic fashion. Mutations in Multidrug Resistance-Like1 (MDR1) reduced acropetal auxin transport in roots by 80% without affecting basipetal transport. Conversely, mutations in MDR4 blocked 50% of basipetal transport without affecting acropetal transport. Developmental and auxin distribution phenotypes associated with these altered auxin flows were studied with a high-resolution morphometric system and confocal microscopy, respectively. Vertically grown mdr1 roots produced positive and negative curvatures threefold greater than the wild type, possibly due to abnormal auxin distribution observed in the elongation zone. However, upon 90° reorientation, mdr1 gravitropism was inseparable from the wild type. Thus, acropetal auxin transport maintains straight growth but contributes surprisingly little to gravitropism. Conversely, vertically maintained mdr4 roots grew as straight as the wild type, but their gravitropism was enhanced. Upon reorientation, curvature in this mutant developed faster, was distributed more basally, and produced a greater total angle than the wild type. An amplified auxin asymmetry may explain the mdr4 hypertropism. Double mutant analysis indicated that the two auxin transport streams are more independent than interdependent. The hypothesis that flavanols regulate MDR-dependent auxin transport was supported by the epistatic relationship of mdr4 to the tt4 phenylpropanoid pathway mutation.

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“…Son moduladores naturales de diferentes proteínas transportadoras al unirse a ellas (140)(141)(142)(143); en el caso de la Pgp, al parecer, los flavonoides interactúan al contrario de los sesquiterpenos, con el sitio de fijación del ATP o dominio NBD y con una región hidrofóbica adyacente a este dominio (144)(145)(146). Varios de estos compuestos son capaces de inhibir el eflujo de medicamentos y revierten el fenotipo MDR en una línea de L. tropica resistente a la daunomicina (147,148).…”

Section: Moduladores De Pgp En Leishmania Sppunclassified

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

et al. 2005

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Actualmente, los parásitos protozoarios son uno de los principales agentes causantes de morbilidad y mortalidad en el mundo, un problema complicado, además, por la aparición de resistencia a medicamentos en estos organismos. La resistencia a medicamentos observada en parásitos protozoarios se debe a diferentes mecanismos como la disminución de la entrada del medicamento a la célula por cambios en el transportador requerido, la pérdida de la activación del medicamento por parte del hospedero, las alteraciones en el blanco del medicamento y la expresión exagerada del transportador múltiple de medicamentos o glicoproteína P (Pgp). En esta revisión, nos centramos en: 1) el papel de las glicoproteínas P (Pgp) de la familia de proteínas ABC (ATP binding cassette) como los transportadores de múltiples medicamentos en la mediación de resistencia en protozoarios, especialmente en Leishmania, y en el desarrollo de resistencia cruzada para medicamentos estructural y funcionalmente no relacionados, y 2) en algunos conceptos relacionados con los mecanismos moduladores que podrían revertir la resistencia a medicamentos por fármacos y productos naturales. Numerosos moduladores o quimiosensibilizadores son conocidos por alterar la capacidad de las glicoproteínas P para mantener concentraciones intracelulares subtóxicas del medicamento; algunos ejemplos incluyen los bloqueadores de los canales de calcio como el verapamilo; sin embargo, se requieren altas concentraciones para una inhibición eficiente y duradera, las cuales producen efectos adversos indeseables. Por tanto, se necesitan más investigaciones relacionadas con los moduladores naturales para Pgp, los cuales podrían presentar menor toxicidad para el hospedero.Palabras clave: Leishmania, protozoos, multirresistencia, glicoproteína P, productos naturales. Leishmania: role of P glycoprotein in drug resistance and reversion strategiesProtozoan parasites are important causative agents of morbidity and mortality throughout the world -a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The di...

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Flavonoid-Related Modulators of Multidrug Resistance: Synthesis, Pharmacological Activity, and Structure−Activity Relationships

Cited by 107 publications

References 32 publications

Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor

Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor

Separating the Roles of Acropetal and Basipetal Auxin Transport on Gravitropism with Mutations in Two Arabidopsis Multidrug Resistance-Like ABC Transporter Genes

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

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