Oroidin Inhibits the Activity of the Multidrug Resistance Target Pdr5p from Yeast Plasma Membranes

Silva, Fernanda R. da; Tessis, Ana Claudia; Ferreira, Patricia F.; Rangel, Luciana P.; Garcia-Gomes, Aline S.; Pereira, Fábio Renato; Berlinck, Roberto G. S.; Muricy, Guilherme; Ferreira‐Pereira, Antônio

doi:10.1021/np1006247

Cited by 18 publications

(15 citation statements)

References 25 publications

(31 reference statements)

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“…However, many other molecules, of synthetic or natural origin, also exhibit this ability. Silva et al [32] demonstrated that oroidin, a derivative of a compound from a sponge, is able to inhibit the catalytic activity of this multidrug transporter with an IC 50 of 20 μM. Rangel et al [15], while studying gallic acid derivatives, observed that decyl gallate has an IC 50 value of 13.5 μM.…”

Section: Resultsmentioning

confidence: 99%

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

et al. 2014

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BackgroundResistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. The Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. The present study investigated the effects of 13 synthetic compounds on Pdr5p.ResultsAmong the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 μM and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 μM. When tested at 100 μM, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.ConclusionsWe have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.

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Section: Resultsmentioning

confidence: 99%

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

et al. 2014

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“…Experimental details, Compound data and characterization, spectra ( 1 H-NMR, 13 C-NMR and HRMS) are included. Bioactivity data (fungal adhesion inhibition) and the chemoinformatic analysis of the SAR trends have been provided.…”

Section: Supporting Information Summarymentioning

confidence: 99%

“…[5] Several previous studies have reported that the natural products (NPs) are a powerful source for biofilm inhibition [6][7][8][9] among which marine natural products gained much attention owing to their structural diversity and ability to inhibit biofilm formation. [10,11] Of the later, Oroidin, isolated from Agelas genus, has been shown to be an effective inhibitor of both P. aeruginosa biofilms, [12] and fungal PDR5 pump, [13] offering an attractive lead pharmacophore for further optimizations.…”

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confidence: 99%

Synthesis and Biological Evaluation of 4/5‐Aroyl‐2‐aminoimidazoles as Microbial Biofilm Inhibitors

et al. 2020

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We had earlier used Oroidin, a 2‐aminoimidazole‐pyrrole natural microbial biofilm inhibitor, as a structural prototype to develop its 4/5‐acyl modified form as an anti‐biofilm lead for further optimization. Herein, as a part of our efforts towards that direction, we report the design, synthesis, as well as anti‐bacterial, anti‐biofilm, and fungal adhesion inhibition activities of various 4/5‐aroyl‐2‐aminoimidazoles. These simplified Oroidin analogues are moderately active against bacterial biofilms and attest to the need for an aliphatic acyl linker that was part of the original 4/5‐acyl modified Oroidin lead. From our studies, protonation propensity of the 2‐aminoimidazole group of the series emerges as an important pre‐requisite for potent antibiofilm activity. Also, the fungal biofilm screening studies identified analogue 8 b as an active molecule.

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“…Compound 33 was moderately active against both methicillin-sensitive and methicillin-resistant strains of S. aureus [25]. This compound may help in the development of new drugs that reverse this dangerous phenotype of pathogenic yeast and fungi [27]. Oroidin (35) was isolated from the marine sponge Agelassventres and inhibited the activity and function of Pdr5P, an enzyme responsible for multidrug resistance phenotype in Saccharomyces cerevisiae.…”

Section: Alkaloidsmentioning

confidence: 99%

Recent Developments in Natural Product-Based Drug Discovery in Tropical Diseases

Lal¹,

Singh²

2016

Studies in Natural Products Chemistry

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Oroidin Inhibits the Activity of the Multidrug Resistance Target Pdr5p from Yeast Plasma Membranes

Cited by 18 publications

References 25 publications

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

Synthesis and Biological Evaluation of 4/5‐Aroyl‐2‐aminoimidazoles as Microbial Biofilm Inhibitors

Recent Developments in Natural Product-Based Drug Discovery in Tropical Diseases

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