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

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D. A. Knorre^1,2,a*, K. V. Galkina¹, T. Shirokovskikh³, A. Banerjee⁴, and R. Prasad⁴

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

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

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

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

^* To whom correspondence should be addressed.

Received July 3, 2020; Revised August 25, 2020; Accepted August 25, 2020

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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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KEY WORDS: multiple drug resistance, yeast, ABC-transporters, signalling, pleiotropic drug resistance

DOI: 10.1134/S0006297920120081

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