scholarly journals Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

2020 ◽  
Vol 8 (10) ◽  
pp. 1574
Author(s):  
Jinxing Song ◽  
Jingwen Zhou ◽  
Lei Zhang ◽  
Rongpeng Li
Keyword(s):  
Drug Resistance ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Efflux Pump ◽  
Mitochondrial Morphology ◽  
Azole Resistance ◽  
Drug Efflux ◽  
Fungal Virulence ◽  
Fungal Pathogenicity ◽  
Drug Efflux Pump

In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.

scholarly journals Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences

2015 ◽  
Vol 35 (4) ◽  
Author(s):  
Ameena J. Haider ◽  
Megan H. Cox ◽  
Natalie Jones ◽  
Alice J. Goode ◽  
Katherine S. Bridge ◽  
...  
Keyword(s):  
Amino Acids ◽  
Drug Resistance ◽  
Protein Trafficking ◽  
Drug Transport ◽  
Protein Targeting ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Drug Efflux ◽  
Evolutionary Analysis ◽  
Drug Efflux Pump

Determining how efflux pumps function is important to understanding their role in drug resistance. We have identified amino acids in a human drug efflux pump that affect interaction with substrate and protein targeting.

Differential Expression of Resistant and Efflux Pump Genes in MDR-TB Isolates

2020 ◽  
Vol 20 (2) ◽  
pp. 271-287 ◽  
Author(s):  
Manaf AlMatar ◽  
Işıl Var ◽  
Begüm Kayar ◽  
Fatih Köksal
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Efflux Pump ◽  
Gene Mutations ◽  
Clinical Isolates ◽  
Pomegranate Juice ◽  
Drug Efflux ◽  
Mdr Tb ◽  
Drug Efflux Pump

Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many. Method: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates. Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

scholarly journals The C2H2 Transcription Factor SltA Contributes to Azole Resistance by Coregulating the Expression of the Drug Target Erg11A and the Drug Efflux Pump Mdr1 in Aspergillus fumigatus

2021 ◽  
Author(s):  
Wenlong Du ◽  
Pengfei Zhai ◽  
Tingli Wang ◽  
Michael J Bromley ◽  
Yuanwei Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Fungal Pathogens ◽  
Efflux Pump ◽  
Antifungal Drugs ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Drug Efflux ◽  
Mobility Shift ◽  
Drug Efflux Pump

The emergence of azole-resistant fungal pathogens has posed a great threat to public health worldwide. Although the molecular mechanism of azole resistance has been extensively investigated, the potential regulators of azole resistance remain largely unexplored. Here we identified a new function of the fungal specific C2H2 zinc finger transcription factor SltA (involved in salt-tolerance pathway) in the regulation of azole resistance of the human fungal pathogen Aspergillus fumigatus. Lack of SltA results in an itraconazole hypersusceptibility phenotype. Transcriptional profiling combined with LacZ reporter analysis and electrophoretic mobility shift assays (EMSA) demonstrate that SltA is involved in its own transcriptional regulation and also regulates the expression of genes related to ergosterol biosynthesis (erg11A, erg13A and erg24A) and drug efflux pumps (mdr1, mfsC and abcE) by directly binding to the conserved 5’-AGGCA-3’ motif in their promoter regions, and this binding is dependent on the conserved cysteine and histidine within the C2H2 DNA binding domain of SltA. Moreover, overexpression of erg11A or mdr1 rescues sltA deletion defects under itraconazole conditions, suggesting that erg11A and mdr1 are related to sltA-mediated itraconazole resistance. Most importantly, deletion of SltA in laboratory-derived and clinical azole-resistant isolates significantly attenuates drug resistance. Collectively, we have identified a new function of the transcription factor SltA in regulating azole resistance by coordinately mediating the key azole target Erg11A and the drug efflux pump Mdr1, and targeting SltA may provide a potential strategy for intervention of clinical azole-resistant isolates to improve the efficiency of currently approved antifungal drugs.

P-glycoprotein drug efflux pump involved in the mechanisms of intrinsic drug resistance in various colon cancer cell lines

1991 ◽  
Vol 41 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Ellen C. Spoelstra ◽  
Henk Dekker ◽  
Gerrit Jan Schuurhuis ◽  
Henricus J. Broxterman ◽  
Jan Lankelma
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Efflux Pump ◽  
Colon Cancer Cell ◽  
Drug Efflux ◽  
P Glycoprotein ◽  
Colon Cancer Cell Lines ◽  
Intrinsic Drug Resistance ◽  
Drug Efflux Pump

Inhibition of RARα2 or Its Downstream Signaling Pathways Decreases Drug Resistance in Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 989-989
Author(s):  
Guido J. Tricot ◽  
Ye Yang ◽  
Fang Xiao ◽  
Maurizio Zangari ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Hedgehog Signaling ◽  
Efflux Pump ◽  
Conflicts Of Interest ◽  
Drug Efflux ◽  
Over Expression ◽  
Drug Efflux Pump

Abstract Abstract 989 Background: We have previously reported that the 30% of newly diagnosed myeloma (MM) patients expressing RARα2, had a significantly inferior outcome. RARα2 expression was also significantly increased in rapidly relapsing myelomas compared to paired baseline samples, indicating the existence at diagnosis of a RARα2 subclone, which is drug-resistant. We further demonstrated that RARα2 expression was significantly higher in MM cell line-derived and primary MM stem cells (MMSC) than in CD138+ bulk MM cells. In this study, we further explore the role of RARα2 in myeloma drug resistance. Materials and methods: RARα2 related drug resistance was evaluated by clonogenic formation assays, using 20,000 MM cells from the RARα2 high-expressing ARK and KMS11 MM cell lines, treated with all-trans retinoic acid (ATRA) (1nM, 10nM), Wnt inhibitor CAY10404 (1 nM, 10nM), Hedgehog inhibitor cyclopamine (1nM, 10nM), bortezomib (1nM, 10nM), as well as doxorubicin (50nM, 100nM), etoposide (50nM, 100nM), and verapamil (50nM). To determine whether inhibition of RARa2 decreased drug resistance, 1.0 × 106 KMS11 cells, made resistant to bortezomib, were transfected with RARα2 shRNA and injected subcutaneously into 20 NOD/SCID mice. The 5TGM1 myeloma mice were used to determine whether targeting RARa2 or its signaling pathways could eliminate MMSC. Results: After serial replating for 6 weeks, MMSCs (CD138- fraction) exhibited greater clonogenic expansion than the control CD138+ fraction, while ATRA, an inhibitor of RARα2, induced potent clonogenic inhibition on MMSC. We also showed in vitro that over-expression of RARα2 in low-expressing MM cell lines, ARP1 and OCI-MY5 resulted in increased clonogenic potential and drug-resistance. In a xenograft myeloma mouse model, knockdown of RARα2 in the KSM11bortezomib-resistant cells decreased resistance to bortezomib. We further identified that RARα2 induced drug resistance by activating the drug efflux pump gene ABCC3 through Wnt and Hedgehog signaling. Inhibition of Wnt (CAY10404) signaling or the ABC transporter by verapamil overcame the drug-resistance in ARP1 and OCI-MY5 cells caused by RARα2 over-expression. Finally, targeting RARa2 or its pathways using ATRA, CAY10404 and cyclopamine significantly reduced the tumor burden as determined by idiotype IgG2 protein levels and increased survival compared to untreated controls (P < 0.05) in the 5TGM1 mice after injection of 5TGM1 MMSC. Conclusion: Over-expression of RARa2 induces drug resistance by activating the drug efflux pump gene ABCC3 through activation of the Wnt and Hedgehog pathways, while inhibition of RARα2 decreases drug resistance. We also provide a possible strategy to eliminate MMSC by targeting RARa2 and/or its downstream targets, such as the Wnt and Hedgehog pathways. Disclosures: No relevant conflicts of interest to declare.

P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽  
1992 ◽  
Vol 51 (18) ◽  
pp. 1427-1437 ◽  
Author(s):  
Akira Tsuji ◽  
Tetsuya Terasaki ◽  
Yasushi Takabatake ◽  
Yoshiyuki Tenda ◽  
Ikumi Tamai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Efflux Pump ◽  
Bovine Brain ◽  
Drug Efflux ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
Drug Efflux Pump

Structure-property correlation in gallic acid and 4-cyanopyridine cocrystal and binding studies with drug efflux pump in bacteria

2021 ◽  
Vol 1225 ◽  
pp. 129279
Author(s):  
Shyam Goswami ◽  
Arabinda Ghosh ◽  
Karmajyoti Borah ◽  
Anupam Mahanta ◽  
Ankur K Guha ◽  
...  
Keyword(s):  
Gallic Acid ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Structure Property ◽  
Binding Studies ◽  
Property Correlation ◽  
Drug Efflux Pump

scholarly journals Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

2014 ◽  
Vol 3 (6) ◽  
pp. 885-896 ◽  
Author(s):  
Thelma Ohene‐Agyei ◽  
Rumana Mowla ◽  
Taufiq Rahman ◽  
Henrietta Venter
Keyword(s):  
Antibacterial Activity ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

2020 ◽  
Vol 13 (654) ◽  
pp. eaay6077
Author(s):  
Apoorva Bhattacharya ◽  
Shravanti Mukherjee ◽  
Poulami Khan ◽  
Shruti Banerjee ◽  
Apratim Dutta ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Chemotherapy Resistance ◽  
Cooperative Interaction ◽  
Drug Efflux ◽  
Cancer Stemness ◽  
Gene Encoding ◽  
Pluripotency Factors ◽  
Tumor Bearing ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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