scholarly journals Deep mutational scan of a drug efflux pump reveals its structure-function landscape

2021 ◽  
Author(s):  
Gianmarco Meier ◽  
Sujani Thavarasah ◽  
Kai Ehrenbolger ◽  
Cedric A.J. Hutter ◽  
Lea M. Hürlimann ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Resistance Mechanism ◽  
Binding Pocket ◽  
Drug Efflux ◽  
Activity Profile ◽  
Substrate Binding Pocket ◽  
High Affinity Binding Site ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump ◽  
Positively Charged

Drug efflux is a common resistance mechanism found in bacteria and cancer cells. Although several structures of drug efflux pumps are available, they provide only limited functional information on the phenomenon of drug efflux. Here, we performed deep mutational scanning (DMS) on the bacterial ATP binding cassette (ABC) transporter EfrCD to determine the drug efflux activity profile of more than 1500 single variants. These systematic measurements revealed that the introduction of negative charges at different locations within the large substrate binding pocket results in strongly increased efflux activity towards positively charged ethidium, while additional aromatic residues did not display the same effect. Data analysis in the context of an inward-facing cryo-EM structure of EfrCD uncovered a high affinity binding site, which releases bound drugs through a peristaltic transport mechanism as the transporter transits to its outward-facing conformation. Finally, we identified substitutions resulting in rapid Hoechst influx without affecting the efflux activity for ethidium and daunorubicin. Hence, single mutations can convert the ABC exporter EfrCD into a drug-specific ABC importer.

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.

Membrane homoeostasis and multidrug resistance in yeast

2008 ◽  
Vol 28 (4) ◽  
pp. 217-228 ◽  
Author(s):  
Sneh Lata Panwar ◽  
Ritu Pasrija ◽  
Rajendra Prasad
Keyword(s):  
Multidrug Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Membrane Lipid ◽  
Major Facilitator Superfamily ◽  
Drug Efflux ◽  
Proper Functioning ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump ◽  
Major Facilitator

The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.

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

scholarly journals A Broad-Specificity Multidrug Efflux Pump Requiring a Pair of Homologous SMR-Type Proteins

2000 ◽  
Vol 182 (8) ◽  
pp. 2311-2313 ◽  
Author(s):  
Donald L. Jack ◽  
Michael L. Storms ◽  
Jason H. Tchieu ◽  
Ian T. Paulsen ◽  
Milton H. Saier
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Resistant Phenotype ◽  
Small Multidrug Resistance ◽  
Drug Efflux Pumps ◽  
Broad Specificity

ABSTRACT The Bacillus subtilis genome encodes seven homologues of the small multidrug resistance (SMR) family of drug efflux pumps. Six of these homologues are paired in three distinct operons, and coexpression in Escherichia coli of one such operon,ykkCD, but not expression of either ykkC orykkD alone, gives rise to a broad specificity, multidrug-resistant phenotype including resistance to cationic, anionic, and neutral drugs.

scholarly journals The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions

2020 ◽  
Vol 202 (22) ◽  
Author(s):  
Tanisha Teelucksingh ◽  
Laura K. Thompson ◽  
Georgina Cox
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Evolutionary Conservation ◽  
Drug Efflux ◽  
Physiological Functions ◽  
Content Type ◽  
Bacterial Physiology ◽  
E Coli ◽  
Drug Efflux Pumps

ABSTRACT Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.

scholarly journals Identification and Evolution of Drug Efflux Pump in Clinical Enterobacter aerogenes Strains Isolated in 1995 and 2003

PLoS ONE ◽  
2008 ◽  
Vol 3 (9) ◽  
pp. e3203 ◽  
Author(s):  
Jacqueline Chevalier ◽  
Céline Mulfinger ◽  
Eric Garnotel ◽  
Pierre Nicolas ◽  
Anne Davin-Régli ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Enterobacter Aerogenes ◽  
Drug Efflux ◽  
Drug Efflux Pump

scholarly journals The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

2018 ◽  
Vol 7 (2) ◽  
pp. 408-419 ◽  
Author(s):  
Takao Nakanishi ◽  
Toshi Menju ◽  
Shigeto Nishikawa ◽  
Koji Takahashi ◽  
Ryo Miyata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells

1999 ◽  
Vol 277 (1) ◽  
pp. F84-F96 ◽  
Author(s):  
Shinya Ito ◽  
Cindy Woodland ◽  
Balázs Sarkadi ◽  
Guido Hockmann ◽  
Scott E. Walker ◽  
...  
Keyword(s):  
Drug Transport ◽  
Diffusion Processes ◽  
Efflux Pump ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Drug Efflux ◽  
Drug Transfer ◽  
P Glycoprotein ◽  
Drug Efflux Pump ◽  
Apical Membranes

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

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