Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

ABSTRACT Multidrug resistance (MDR) in Enterobacter aerogenes can be mediated by induction of MarA, which is triggered by certain antibiotics and phenolic compounds. In this study, we identified the gene encoding RamA, a 113-amino-acid regulatory protein belonging to the AraC-XylS transcriptional activator family, in the Enterobacter aerogenes ATCC 13048 type strain and in a clinical multiresistant isolate. Overexpression of RamA induced an MDR phenotype in drug-susceptible Escherichia coli JM109 and E. aerogenes ATCC 13048, as demonstrated by 2- to 16-fold-increased resistance to β-lactams, tetracycline, chloramphenicol, and quinolones, a decrease in porin production, and increased production of AcrA, a component of the AcrAB-TolC drug efflux pump. We show that RamA enhances the transcription of the marRAB operon but is also able to induce an MDR phenotype in a mar-deleted strain. We demonstrate here that RamA is a transcriptional activator of the Mar regulon and is also a self-governing activator of the MDR cascade.

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The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.19.8822 ◽

1994 ◽

Vol 91 (19) ◽

pp. 8822-8826 ◽

Cited By ~ 403

Author(s):

G. J. Zaman ◽

M. J. Flens ◽

M. R. van Leusden ◽

M. de Haas ◽

H. S. Mulder ◽

...

Keyword(s):

Plasma Membrane ◽

Multidrug Resistance ◽

Efflux Pump ◽

Drug Efflux ◽

Drug Efflux Pump

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Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

10.1101/2020.06.26.173484 ◽

2020 ◽

Author(s):

Yaojun Tong ◽

Nuo Sun ◽

Xiangming Wang ◽

Qi Wei ◽

Yu Zhang ◽

...

Keyword(s):

Candida Albicans ◽

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Multidrug Efflux Pump ◽

Drug Efflux Pumps ◽

Major Facilitator

AbstractClinical use of antimicrobials faces great challenges from the emergence of multidrug resistant (MDR) pathogens. The overexpression of drug efflux pumps is one of the major contributors to MDR. It is considered as a promising approach to overcome MDR by reversing the function of drug efflux pumps. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to multidrug resistance. Here we report a counterintuitive case of reversing multidrug resistance in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria, and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. It results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time (MST) of mice with a blood-borne dissemination of Mdr1p overexpressed multidrug resistant candidiasis. This study provided a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.

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Human hepatocellular carcinoma cell lines exhibit multidrug resistance unrelated to MRD1 gene expression

Journal of Cell Science ◽

10.1242/jcs.98.3.317 ◽

1991 ◽

Vol 98 (3) ◽

pp. 317-322

Author(s):

D.W. Shen ◽

Y.G. Lu ◽

K.V. Chin ◽

I. Pastan ◽

M.M. Gottesman

Keyword(s):

Hepatocellular Carcinoma ◽

Multidrug Resistance ◽

Cancer Cells ◽

Cell Lines ◽

Actinomycin D ◽

Efflux Pump ◽

Mdr1 Gene ◽

Drug Efflux ◽

P Glycoprotein ◽

Drug Efflux Pump

Multidrug resistance of human cancer cells may result from expression of P-glycoprotein, the product of the MRD1 gene, acting as an energy-dependent drug efflux pump. However, direct evidence that expression of the MDR1 gene contributes to the multidrug resistance of human liver carcinomas has not been established. In this study, we tested five cell lines derived from human hepatocellular carcinomas for sensitivity to a variety of drugs used widely as anticancer agents; these included vinblastine, doxorubicin, actinomycin D, mitomycin C, 5-fluorouracil, 6-mercaptopurine, melphalan, methotrexate, cis-platinum and etoposide (VP-16). All five hepatoma cell lines were resistant at different levels to these chemicals compared to human KB cells. Although it has been demonstrated that resistance to vinblastine, colchicine, doxorubicin and actinomycin D in human multidrug-resistant cells is associated with overexpression of P-glycoprotein, very little expression of P-glycoprotein was found in these human hepatoma cells. Neither verapamil nor quinidine, inhibitors of the drug efflux pump, were able to overcome multidrug resistance in hepatoma cells. These results indicate that the multidrug resistance phenotype in human hepatocellular carcinoma cells cannot be attributed to expression of the MDR1 gene, but that novel mechanisms may account for the resistance of these cancer cells.

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Membrane homoeostasis and multidrug resistance in yeast

Bioscience Reports ◽

10.1042/bsr20080071 ◽

2008 ◽

Vol 28 (4) ◽

pp. 217-228 ◽

Cited By ~ 17

Author(s):

Sneh Lata Panwar ◽

Ritu Pasrija ◽

Rajendra Prasad

Keyword(s):

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Membrane Lipid ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Proper Functioning ◽

Drug Efflux Pumps ◽

Drug Efflux Pump ◽

Major Facilitator

The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.

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Lectin detection of cell surface saccharides remodeling induced by development of P-glycoprotein mediated multidrug resistance phenotype in L1210 leukemia cells

Acta Chimica Slovaca ◽

10.2478/acs-2014-0010 ◽

2014 ◽

Vol 7 (1) ◽

pp. 52-56 ◽

Cited By ~ 2

Author(s):

Mário Šereš ◽

Lucia Pavlíková ◽

Zdena Sulová ◽

Albert Breier

Keyword(s):

Multidrug Resistance ◽

Cell Surface ◽

Efflux Pump ◽

L1210 Cell ◽

Leukemia Cells ◽

Drug Efflux ◽

L1210 Leukemia ◽

P Glycoprotein ◽

Drug Efflux Pump ◽

State Of Art

Abstract P-glycoprotein is an ATP dependent drug efflux pump the expression of which is responsible for strong depression of cell sensitivities to large group of structurally unrelated substances in neoplastic cells. We found that the expression of this protein in mice leukemia cells L1210 is associated with massive remodeling of cell surface saccharides. This remodeling is consistent with the alteration of cellular contents of UDP-sugars, glycogen and glycoproteins when P-gp positive and P-gp negative L1210 cell variants were compared. The current paper is focused on bringing the state of art information about this topic.

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