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Do Multiple Drug Resistance Transporters Interfere with Cell Functioning under Normal Conditions?

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Abstract

Eukaryotic cells rely on multiple mechanisms to protect themselves from exogenous toxic compounds. For instance, cells can limit penetration of toxic molecules through the plasma membrane or sequester them within the specialized compartments. Plasma membrane transporters with broad substrate specificity confer multiple drug resistance (MDR) to cells. These transporters efflux toxic compounds at the cost of ATP hydrolysis (ABC-transporters) or proton influx (MFS-transporters). In our review, we discuss the possible costs of having an active drug-efflux system using yeast cells as an example. The pleiotropic drug resistance (PDR) subfamily ABC-transporters are known to constitutively hydrolyze ATP even without any substrate stimulation or transport across the membrane. Besides, some MDR-transporters have flippase activity allowing transport of lipids from inner to outer lipid layer of the plasma membrane. Thus, excessive activity of MDR-transporters can adversely affect plasma membrane properties. Moreover, broad substrate specificity of ABC-transporters also suggests the possibility of unintentional efflux of some natural metabolic intermediates from the cells. Furthermore, in some microorganisms, transport of quorum-sensing factors is mediated by MDR transporters; thus, overexpression of the transporters can also disturb cell-to-cell communications. As a result, under normal conditions, cells keep MDR-transporter genes repressed and activate them only upon exposure to stresses. We speculate that exploiting limitations of the drug-efflux system is a promising strategy to counteract MDR in pathogenic fungi.

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Abbreviations

ABC:

ATP-binding cassette

QS:

quorum sensing

MDR:

multiple drug resistance

MFS:

major facilitator superfamily

PDR:

pleiotropic drug resistance

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Acknowledgements

We are grateful to V. P. Skulachev for stimulating discussions on basic principles of multiple drug resistance during the seminars on bioenergetics organized by him.

Funding

DK and RP acknowledge support from the joint Indo-Russian grant INT/RUS/RFBR/P-328 (India)/Russian Foundation for Basic Research [grant 18-54-45001 IND-A (Russia)]. The study was also supported by the Russian Science Foundation (grant 20-14-00268, for DK and KG, the chapter on the bioenergetic cost of PDR-transporters). This work was also supported by Moscow State University Grant for Leading Scientific Schools “Depository of the Living Systems” in the framework of the MSU Development Program.

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Authors and Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    D. A. Knorre & K. V. Galkina

  2. Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia

    D. A. Knorre

  3. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia

    T. Shirokovskikh

  4. Amity Institute of Biotechnology and Amity Institute of Integrative Sciences and Health, Amity University Haryana, Amity Education Valley, 122413, Gurugram, India

    A. Banerjee & R. Prasad

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  1. D. A. Knorre
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  2. K. V. Galkina
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  3. T. Shirokovskikh
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  4. A. Banerjee
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  5. R. Prasad
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Correspondence to D. A. Knorre.

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The authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

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Knorre, D.A., Galkina, K.V., Shirokovskikh, T. et al. Do Multiple Drug Resistance Transporters Interfere with Cell Functioning under Normal Conditions?. Biochemistry Moscow 85, 1560–1569 (2020). https://doi.org/10.1134/S0006297920120081

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  • DOI: https://doi.org/10.1134/S0006297920120081

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