ATP-binding Cassette Superfamily Research Articles

Impacts of ABCG2 loss of function variant (p. Gln141Lys, c.421 C > A, rs2231142) on lipid levels and statin efficiency: a systematic review and meta-analysis

BackgroundThe latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol efflux. This study investigates whether the function variant loss within ABCG2 (rs2231142) impacts lipid levels and statin efficiency.MethodsPubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until November 18, 2023.ResultsFifteen studies (34,150 individuals) were included in the analysis. The A allele [Glu141Lys amino acid substitution was formed by a transversion from cytosine (C) to adenine (A)] of rs2231142 was linked to lower levels of high-density lipoprotein cholesterol (HDL-C), and higher levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). In addition, the A allele of rs2231142 substantially increased the lipid-lowering efficiency of rosuvastatin in Asian individuals with dyslipidemia. Subgroup analysis indicated that the impacts of rs2231142 on lipid levels and statin response were primarily in Asian individuals.ConclusionsThe ABCG2 rs2231142 loss of function variant significantly impacts lipid levels and statin efficiency. Preventive use of rosuvastatin may prevent the onset of coronary artery disease (CAD) in Asian individuals with dyslipidemia.

Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1.

The expression of drug efflux pump ABCB1/P-glycoprotein (P-gp), a transmembrane protein belonging to the ATP-binding cassette superfamily, is a leading cause of multidrug resistance (MDR). We previously curated a dataset of structurally diverse and selective inhibitors of ABCB1 to develop a pharmacophore model that was used to identify four novel compounds, which we showed to be potent and efficacious inhibitors of ABCB1. Here, we dock the inhibitors into a model structure of the human transporter and use molecular dynamics (MD) simulations to report the conformational dynamics of human ABCB1 induced by the binding of the inhibitors. The binding hypotheses are compared to the wider curated dataset and those previously reported in the literature. Protein-ligand interactions and MD simulations are in good agreement and, combined with LipE profiling, statistical and pharmacokinetic analyses, are indicative of potent and selective inhibition of ABCB1.

Discovery of a Novel Integrative Conjugative Element ICEAplChn2 Related to SXT/R391 in Actinobacillus pleuropneumoniae.

Objective: The objective of this study was to characterize ICEAplChn2, a novel SXT/R391-related integration and conjugation element (ICE) carrying 19 drug resistance genes, in a clinical isolate of Actinobacillus pleuropneumoniae from swine. Methods: Whole genome sequencing (WGS) of A. pleuropneumoniae CP063424 strain was completed using a combination of third-generation PacBio and second-generation Illumina. The putative ICE was predicted by the online tool ICEfinder. ICEAplChn2 was analyzed by PCR, conjugation experiments, and bioinformatics tools. Results: A. pleuropneumoniae CP063424 strain exhibited high minimum inhibitory concentrations of clindamycin (1,024 mg/L). The WGS data revealed that ICEAplChn2, with a length of 167,870 bp and encoding 151 genes, including multiple antibiotic resistance genes such as erm(42), VanE, LpxC, dfrA1, golS, aadA3, EreA, dfrA32, tetR(C), tet(C), sul2, aph(3)″-lb, aph(6)-l, floR, dfrA, ANT(3″)-IIa, catB11, and VanRE, was found to be related to the SXT/R391 family on the chromosome of A. pleuronipneumoniae CP063424. The circular intermediate of ICEAplChn2 was detected by PCR, but conjugation experiments showed that it was not self-transmissible. Conclusions: To our knowledge, ICEAplChn2 is the longest member with the most resistance genes in the SXT/R391 family. Meanwhile, ATP-binding cassette superfamily was found to be inserted in the ICEAplChn2 and possessed a new insertion region, which is the first description in the SXT/R391 family.

Purification and characterization of Cdr1, the drug-efflux pump conferring azole resistance in Candida species

Candida albicans and C. glabrata express exporters of the ATP-binding cassette (ABC) superfamily and address them to their plasma membrane to expel azole antifungals, which cancels out their action and allows the yeast to become multidrug resistant (MDR). In a way to understand this mechanism of defense, we describe the purification and characterization of Cdr1, the membrane ABC exporter mainly responsible for such phenotype in both species. Cdr1 proteins were functionally expressed in the baker yeast, tagged at their C-terminal end with either a His-tag for the glabrata version, cgCdr1-His, or a green fluorescent protein (GFP) preceded by a proteolytic cleavage site for the albicans version, caCdr1-P-GFP. A membrane Cdr1-enriched fraction was then prepared to assay several detergents and stabilizers, probing their level of extraction and the ATPase activity of the proteins as a functional marker. Immobilized metal-affinity and size-exclusion chromatographies (IMAC, SEC) were then carried out to isolate homogenous samples. Overall, our data show that although topologically and phylogenetically close, both proteins display quite distinct behaviors during the extraction and purification steps, and qualify cgCdr1 as a good candidate to characterize this type of proteins for developing future inhibitors of their azole antifungal efflux activity.

Dose-Dependent Genetic Resistance to Azole Fungicides Found in the Apple Scab Pathogen.

The evolution of azole resistance in fungal pathogens presents a major challenge in both crop production and human health. Apple orchards across the world are faced with the emergence of azole fungicide resistance in the apple scab pathogen Venturia inaequalis. Target site point mutations observed in this fungus to date cannot fully explain the reduction in sensitivity to azole fungicides. Here, polygenic resistance to tebuconazole was studied across a population of V. inaequalis. Genotyping by sequencing allowed Quantitative Trait Loci (QTLs) mapping to identify the genetic components controlling this fungicide resistance. Dose-dependent genetic resistance was identified, with distinct genetic components contributing to fungicide resistance at different exposure levels. A QTL within linkage group seven explained 65% of the variation in the effective dose required to reduce growth by 50% (ED50). This locus was also involved in resistance at lower fungicide doses (ED10). A second QTL in linkage group one was associated with dose-dependent resistance, explaining 34% of variation at low fungicide doses (ED10), but did not contribute to resistance at higher doses (ED50 and ED90). Within QTL regions, non-synonymous mutations were observed in several ATP-Binding Cassette and Major Facilitator SuperFamily transporter genes. These findings provide insight into the mechanisms of fungicide resistance that have evolved in horticultural pathogens. Identification of resistance gene candidates supports the development of molecular diagnostics to inform management practices.

Genome-Wide Identification and Analysis of the ABCF Gene Family in Triticum aestivum.

The ATP-binding cassette (ABC) superfamily of proteins is a group of evolutionarily conserved proteins. The ABCF subfamily is involved in ribosomal synthesis, antibiotic resistance, and transcriptional regulation. However, few studies have investigated the role of ABCF in wheat (Triticum aestivum) immunity. Here, we identified 18 TaABCFs and classified them into four categories based on their domain characteristics. Functional similarity between Arabidopsis and wheat ABCF genes was predicted using phylogenetic analysis. A comprehensive genome-wide analysis of gene structure, protein motifs, chromosomal location, and cis-acting elements was also performed. Tissue-specific analysis and expression profiling under temperature, hormonal, and viral stresses were performed using real-time quantitative reverse transcription polymerase chain reaction after randomly selecting one gene from each group. The results revealed that all TaABCF genes had the highest expression at 25 °C and responded to methyl jasmonate induction. Notably, TaABCF2 was highly expressed in all tissues except the roots, and silencing it significantly increased the accumulation of Chinese wheat mosaic virus or wheat yellow mosaic virus in wheat leaves. These results indicated that TaABCF may function in response to viral infection, laying the foundation for further studies on the mechanisms of this protein family in plant defence.

ABCB1 Regulates Immune Genes in Breast Cancer.

Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and immune genes in breast cancer has not been widely studied. Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2+ breast cancer was established to investigate the association between ABCB1 and immune genes in breast cancer. Expression of ABCB1 increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. ABCB1 is positively correlated with IL6, CSF1, CSF3, and PTGS2. In the HER2+ stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were more abundant than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well controlled after paclitaxel-trastuzumab combined therapy. ABCB1 was a poor predictor of HER2+ LN- breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.

Evaluation of the FDA-approved kinase inhibitors to uncover the potential repurposing candidates targeting ABC transporters in multidrug-resistant cancer cells: an in silico approach

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors’ probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters. Communicated by Ramaswamy H. Sarma

CWHM-974 is a fluphenazine derivative with improved antifungal activity against Candida albicans due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms.

Multidrug resistance (MDR) transporters such as ATP-Binding Cassette (ABC) and Major Facilitator Superfamily proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against Candida spp. compared to the fluphenazine and with activity against Candida spp. with reduced fluconazole susceptibility due to increased MDR transporters. Here, we show that the improved C. albicans activity is because fluphenazine induces its own resistance by triggering expression of Candida drug resistance (CDR) transporters while CWHM-974 induces expression but does not appear to be a substrate for the transporters or is insensitive to their effects through other mechanisms. We also found that fluphenazine and CWHM-974 are antagonistic with fluconazole in C. albicans but not in C. glabrata, despite inducing CDR1 expression to high levels. Overall, CWHM-974 is one of the few examples of a molecule in which relatively small structural modifications significantly reduced susceptibility to multidrug transporter-mediated resistance.

TICBase: Integrated Resource for Data on Drug and Environmental Chemical Interactions with Mammalian Drug Transporters.

Environmental health science seeks to predict how environmental toxins, chemical toxicants, and prescription drugs accumulate and interact within the body. Xenobiotic transporters of the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies are major determinants of the uptake and disposition of xenobiotics across the kingdoms of life. The goal of this study was to integrate drug and environmental chemical interactions of mammalian ABC and SLC proteins in a centralized, integrative database. We built upon an existing publicly accessible platform-the "TransPortal"-which was updated with novel data and searchable features on transporter-interfering chemicals from manually curated literature data. The integrated resource TransPortal-TICBase (https://transportal.compbio.ucsf.edu) now contains information on 46 different mammalian xenobiotic transporters of the ABC- and SLC-type superfamilies, including 13 newly added rodent and 2 additional human drug transporters, 126 clinical drug-drug interactions, and a more than quadrupled expansion of the initial in vitro chemical interaction data from 1,402 to 6,296 total interactions. Based on our updated database, environmental interference with major human and rodent drug transporters occurs across the ABC- and SLC-type superfamilies, with kinetics indicating that some chemicals, such as the ionic liquid 1-hexylpyridinium chloride and the antiseptic chlorhexidine, can act as strong inhibitors with potencies similar or even higher than pharmacological model inhibitors. The new integrated web portal serves as a central repository of current and emerging data for interactions of prescription drugs and environmental chemicals with human drug transporters. This archive has important implications for predicting adverse drug-drug and drug-environmental chemical interactions and can serve as a reference website for the broader scientific community of clinicians and researchers.

Dampening HOTAIR sensitizes the gastric cancer cells to oxaliplatin through miR-195-5p and ABCG2 pathway.

Long non-coding RNAs (lncRNA) have an extensive role in the progression and chemoresistance of gastric cancer (GC). Deeply study the regulatory role of lncRNAs could provide potential therapeutic targets. The aim of this study is to explore the regulatory role of HOTAIR in the progression and oxaliplatin resistance of GC. The expression of HOTAIR in GC and cell lines were detected by using qRT-PCR. Cell proliferation and apoptosis were analysed by CCK-8, EdU incorporation and flow cytometry. Luciferase reporter assay was used to identify the interaction between HOTAIR and ABCG2 (ATP-binding cassette (ABC) superfamily G member 2, ABCG2) via miR-195-5p. The regulatory functions were verified by using molecular biology experiments. HOTAIR was significantly overexpressed in GC and associated with poor prognosis. Knock-down of HOTAIR inhibited the GC cells proliferation and oxaliplatin resistance, while overexpression of HOTAIR showed opposite functions. Further studies found that HOTAIR acted as a competing endogenous RNA (ceRNA) to absorb miR-195-5p and elevated the expression of ABCG2, which leads to resistance of GC cells to oxaliplatin. Taken together, our findings demonstrated that HOTAIR regulates ABCG2 induced resistance of GC to oxaliplatin through miR-195-5p signalling and illustrate the great potential of developing new therapeutic targets for GC patients.

Targeting MAGI2-AS3-modulated Akt-dependent ATP-binding cassette transporters as a possible strategy to reverse temozolomide resistance in temozolomide-resistant glioblastoma cells.

Drug resistance is a major impediment to the successful treatment of glioma. This study aimed to elucidate the effects and mechanisms of the long noncoding RNA membrane-associated guanylate kinase inverted-2 antisense RNA 3 (MAGI2-AS3) on temozolomide (TMZ) resistance in glioma cells. MAGI2-AS3 expression in TMZ-resistant glioblastoma (GBM) cells was analyzed using the Gene Expression Omnibus data set GSE113510and quantitative real-time PCR (qRT-PCR). Cell viability and TMZ half-maximal inhibitory concentration values were determined using the MTT assay. Apoptosis and cell cycle distribution were evaluated using flow cytometry. The expression of multidrug resistance 1 (MDR1), ATP-binding cassette superfamily G member 2 (ABCG2), protein kinase B (Akt), and phosphorylated Akt was detected using qRT-PCR and/or western blot analysis. MAGI2-AS3 was expressed at low levels in TMZ-resistant GBM cells relative to that in their parental cells. MAGI2-AS3 re-expression alleviated TMZ resistance in TMZ-resistant GBM cells. MAGI2-AS3 overexpression also accelerated TMZ-induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2-AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2-AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2-AS3 on TMZ resistance. MAGI2-AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2-AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.

Multidrug resistance of Rhizoctonia solani determined by enhanced efflux for fungicides

Plant pathogens can develop multidrug resistance (MDR) through metabolomic and efflux activities. Although MDR has been observed in the field, its mechanisms are yet to be further studied. MDR in Rhizoctonia solani induced by the uncoupler SYP-14288, which involved efflux transporters including ATP binding cassette (ABC) and major facilitator superfamily (MFS) have been reported in our previous study. To confirm this, corresponding genes of the wild-type R. solani X19 and its derived MDR mutant X19–7 were compared through transcriptomics, RNA-Seq data validation, and heterologous expression. Genes encoding six ABC transporters and seven MFS transporters were identified to be associated with MDR and mostly showed a constitutively higher expression in X19–7 than in X19 regardless of SYP-14288 treatment. Eight ABC transporter-encoding genes and eight MFS transporter-encoding genes were further characterized by transferring into Saccharomyces cerevisiae. The sensitivity of transformants containing either ABC transporter-encoding gene AG1IA_06082 and MFS transporter-encoding gene AG1IA_08645 was significantly decreased in responses to fungicides having various modes of action including SYP-14288, fluazinam, chlorothalonil, and difenoconazole, indicating that these two genes were related to MDR. The roles of two genes were further confirmed by successfully detecting their protein products and high accumulation of SYP-14288 in yeast transformants. Thus, ABC and MFS transporters contributed to the development of MDR in R. solani. The result helps to understand the cause and mechanisms that influence the efficient use of fungicide.

Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation.

Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.

The Role of ATP-Binding Cassette Proteins in Stem Cell Pluripotency.

Pluripotent stem cells (PSCs) are highly proliferative cells that can self-renew indefinitely in vitro. Upon receiving appropriate signals, PSCs undergo differentiation and can generate every cell type in the body. These unique properties of PSCs require specific gene expression patterns that define stem cell identity and dynamic regulation of intracellular metabolism to support cell growth and cell fate transitions. PSCs are prone to DNA damage due to elevated replicative and transcriptional stress. Therefore, mechanisms to prevent deleterious mutations in PSCs that compromise stem cell function or increase the risk of tumor formation from becoming amplified and propagated to progenitor cells are essential for embryonic development and for using PSCs including induced PSCs (iPSCs) as a cell source for regenerative medicine. In this review, we discuss the role of the ATP-binding cassette (ABC) superfamily in maintaining PSC homeostasis, and propose how their activities can influence cellular signaling and stem cell fate decisions. Finally, we highlight recent discoveries that not all ABC family members perform only canonical metabolite and peptide transport functions in PSCs; rather, they can participate in diverse cellular processes from genome surveillance to gene transcription and mRNA translation, which are likely to maintain the pristine state of PSCs.

ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer-In Silico and Wet Analysis.

ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein-protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis.

Abrogation of efflux pump activity, biofilm formation, and immune escape by candidacidal geraniol in emerging superbug, Candida auris.

During the last decade, Candida auris emerged as a threatening human fungal pathogen that notably caused outbreaks around the globe with high mortality. Considering C. auris species as newly discovered fungi, the evolutionary features remain elusive. The antifungal resistance which is a norm in C. auris underlines the need for innovative therapeutic options. ATP Binding Cassette (ABC) superfamily efflux pumps overexpression and biofilms are known to be major contributors to multidrug resistance (MDR) in C. auris. Therefore, herein, we investigated the antifungal potential of geraniol (Ger) as a promising naturalcompound in the fight against MDR C. auris. Our experiments proved that Ger was fungicidal in nature and impaired rhodamine 6G (R6G) efflux, confirming the specific effect on ABC transporters. Kinetic studies unravelled the competitive mode of inhibition by Ger for R6G efflux since the apparent Km increased with no change in Vmax value. Mechanistic insights also revealed that Ger depleted ergosterol content in C. auris. Furthermore, Ger led to inhibition in biofilm formation as evident from crystal violet staining, biofilm metabolic and biomass measurements. Additionally, enhanced survival of Caenorhabditis elegans model after C. auris infection demonstrated the in vivo efficacy of Ger. Lastly, the in vivo efficacy was confirmed from a THP-1 cell line model which depicted enhanced macrophage-mediated killing in the presence of Ger. Modulation of C. auris efflux pump activity and biofilm formation by Ger represents a promising approach to combatMDR. Together, this study demonstrated the potential therapeutic insights of Ger as a promising addition to the antifungal armamentarium required to treat emerging and resistant C. auris.

Designing of new tetrahydro-β-carboline-based ABCG2 inhibitors using 3D-QSAR, molecular docking, and DFT tools

Human ATP-binding cassette superfamily G member 2 (ABCG2) protein is a member of the ABC transporter family, which is responsible for multidrug resistance (MDR) in cancerous cells. MDR reduces the effectiveness of chemotherapy in breast cancer, which is one of the leading causes of death in women globally. MDR in cancer cells is one of the immediate signs of progression of resistance; thus, various anticancer drugs can be designed. To reduce MDR, we utilized the tetrahydro-β-carboline (THβC) compound library. We accomplished a three-dimensional quantitative structure-activity relationship (3D-QSAR), scaffold hopping to design a new library of compounds of THβC, and further molecular docking, induced-fit docking (IFD), molecular mechanics energies combined with generalized born and surface area continuum solvation (MM-GBSA), drug-like features, ADMET properties, and density functional theory (DFT) studies were performed. From these studies, the best 3D-QSAR model (r2 = 0.99, q2 = 0.92) was found, and the necessity of electrostatic, steric, and hydrophobic field effects were determined that could modulate bioactivity. Moreover, based on electrostatic, steric, and hydrophobic field notations, new THβC derivatives (3409) were designed. These findings might provide new insight for researchers to perform in vitro and in vivo studies for better antagonists against MDR in treating breast cancer.Communicated by Ramaswamy H. Sarma

Human ATP Binding Cassette Superfamily and Profiling Subfamily-Specific Motif for Classification

The ATP binding cassette (ABC) transporter superfamily is ubiquitous in all three domains of life. The cellular and molecular functions of ABC transporters are diverse and essential to all living organisms. In human, mutations associated with ABC transporters are known to cause many genetic diseases. Although the members of ABC transporter superfamily share common sequential feature, the subfamily recognition is not a trivial task because of its domain complexity. The functional annotation begins with subfamily recognition. Here, we showed that a motif profiling provides simple and intuitive approach to recognize the subfamily level. Along with relation to the structural feature, the motif profiling approach will be a guide to annotate and understand molecular functions of subfamilies with a big superfamily

In Silico Identification and In Vitro Evaluation of New ABCG2 Transporter Inhibitors as Potential Anticancer Agents

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.