Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

Abstract

Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

“…The majority of these proteins belong to the mammalian adenosine triphosphate (ATP)-binding cassette (ABC) family of transporters. There are 48 types of functionally diverse human transporters, which have been divided into 7 distinct subfamilies (A-G) on the basis of their structural relatedness and domain organization [ 29 ]. Thus far, 16 types of ABC transporters are directly and/or indirectly linked to multidrug resistance in liver, kidney, pancreas, and other types of cancer ( Table 1 ) [ 30 , 31 , 32 ].…”

“…The most extensively studied ABC transporters are the ABCB1 (permeability glycoprotein/MDR1), ABCC1 (multidrug resistance-associated protein-1, MRP1), and ABCG2 (breast cancer resistance protein (BCRP)) [ 32 ]. Their main ability is to recognize chemotherapeutic agents after their internalization within the plasma membrane and use the energy produced via ATP hydrolysis in order to expel drug molecules out of the cells, thereby decreasing bioavailability and increasing drug resistance [ 29 , 33 ]. Transportation of drugs across cells occurs through multiple processes, such as passive diffusion, facilitated or active transport, or pinocytosis.…”

Yeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughput

“…The yor1 Δ mutation caused sensitivity only to tunicamycin. Pdr11p, a pleiotropic drug resistance (PDR) family member involved in sterol uptake ( 21 , 63 ), was identified among mutations that conferred sensitivity to artesunate, captan, chlorothalonil, difenoconazole, N -phenylanthranilic acid, tamoxifen, and tunicamycin. The PDR11 paralog, AUS1, involved in sterol uptake ( 21 ), was not represented among depleted strains.…”

“…The PDR11 paralog, AUS1, involved in sterol uptake ( 21 ), was not represented among depleted strains. We also identified Nft1p, a putative transporter of the multidrug resistance protein (MRP) subfamily ( 22 , 63 ), as a candidate exporter for epoxiconazole, tebuconazole, difenoconazole, and 5-fluorocytosine.…”

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

“…The overexpression of drug efflux pumps belonging to the ABC superfamily is also a frequent cause of resistance to antifungals [ 95 ]. MDR in yeasts seems to be related to pleiotropic drug resistance (PDR) subfamily and major facilitator superfamily (MFS) transporters [ 96 ] even though their mechanisms remain unclear [ 97 , 98 ]. Azole resistance is a major concern for treatment of infections with Aspergillus fumigatus , a saprophytic mold that can cause a range of clinical syndromes ranging from allergic conditions to acute and chronic invasive pulmonary aspergillosis, especially in immunosuppressed patients [ 99 ].…”