Computational simulations to study the kinetics of drug efflux via multidrug resistant membrane proteins expressed in confluent cell monolayers: a critical evaluation of different models employed, data fitting techniques and global optimization strategies

2021 ◽  
Author(s):  
Deep Agnani
Keyword(s):  
Global Optimization ◽  
Membrane Proteins ◽  
Critical Evaluation ◽  
Data Fitting ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Computational Simulations ◽  
Cell Monolayers ◽  
Confluent Cell ◽  
Kinetics Of

scholarly journals Multidrug resistant P-glycoprotein positive L1210/VCR cells are also cross-resistant to cisplatin via a mechanism distinct from P-glycoprotein-mediated drug efflux activity

2009 ◽  
Vol 28 (4) ◽  
pp. 391-403 ◽  
Author(s):  
L. Gibalová ◽  
J. Sedlák ◽  
M. Labudová ◽  
M. Barančík ◽  
A. Reháková ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Drug Efflux ◽  
P Glycoprotein

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 Linking 3D and 2D binding kinetics of membrane proteins by multiscale simulations

2014 ◽  
Vol 23 (12) ◽  
pp. 1789-1799 ◽  
Author(s):  
Zhong-Ru Xie ◽  
Jiawen Chen ◽  
Yinghao Wu
Keyword(s):  
Membrane Proteins ◽  
Binding Kinetics ◽  
Multiscale Simulations ◽  
Kinetics Of

Association between ABCB1 Polymorphisms and Artesunate–Mefloquine Treatment Responses of Patients with Falciparum Malaria on the Thailand–Myanmar Border

2021 ◽  
Author(s):  
Kanyarat Boonprasert ◽  
Nanthawat Kosa ◽  
Poonuch Muhamad ◽  
Anurak Cheoymang ◽  
Kesara Na-Bangchang
Keyword(s):  
Falciparum Malaria ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Antimalarial Treatment ◽  
Mutant Genotype ◽  
Genes Encoding ◽  
Treatment Responses ◽  
Endemic Areas ◽  
The Impact ◽  
Larger Sample

A decrease in the clinical efficacy of a 3-day artesunate–mefloquine combination treatment was reported in the areas of multidrug-resistant Plasmodium falciparum along the Thailand–Myanmar border. The current study investigated the possible contribution of genetic polymorphisms of the three major genes encoding drug efflux transporters, ABCB1, ABCG2, and ABCC1, to responses to the aforementioned treatment in 91 patients with acute uncomplicated falciparum malaria residing along the Thailand–Myanmar border. Patients carrying homozygous mutant genotype ABCB1 c.1236C>T (TT) were found to have a three-times higher chance of successful treatment with this combination compared with other genotypes (CC and CT). Furthermore, whole blood mefloquine concentrations in these patients with the TT genotype were significantly lower than those of patients carrying the CC genotype. Patients with heterozygous mutant genotype (CT), however, were three-times more likely to experience treatment failure. No significant association was found with the ABCG2 and ABCC1 gene polymorphisms. The results suggest that ABCB1 c.1236CT polymorphisms could be useful genetic markers for predicting responses to the 3-day artesunate–mefloquine treatment; however, studies using larger sample sizes in different malaria-endemic areas are necessary to confirm this finding. This study highlights the impact of pharmacogenetic factors on antimalarial treatment responses and the basis for the application of control policies in various malaria-endemic areas.

A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections

2020 ◽  
pp. 106002802097400
Author(s):  
Kathleen C. Blomquist ◽  
David E. Nix
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Data ◽  
Therapeutic Potential ◽  
Data Extraction ◽  
Relevant Literature ◽  
Acquired Resistance ◽  
Critical Evaluation ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Study Selection

Objective: This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms. Data Sources: An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa. Study Selection and Data Extraction: Relevant published articles and package inserts were reviewed for inclusion. Data Synthesis: Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections. Relevance to Patient Care and Clinical Practice: Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections. Conclusions: Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.

scholarly journals Synthetic and genetic dimers as quantification ruler for single-molecule counting with PALM

2019 ◽  
Vol 30 (12) ◽  
pp. 1369-1376 ◽  
Author(s):  
Tim N. Baldering ◽  
Marina S. Dietz ◽  
Karl Gatterdam ◽  
Christos Karathanasis ◽  
Ralph Wieneke ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Single Molecule ◽  
Fusion Proteins ◽  
Fluorescent Proteins ◽  
Superresolution Microscopy ◽  
Superresolution Imaging ◽  
Molecular Information ◽  
Kinetics Of

How membrane proteins oligomerize determines their function. Superresolution microscopy can report on protein clustering and extract quantitative molecular information. Here, we evaluate the blinking kinetics of four photoactivatable fluorescent proteins for quantitative single-molecule microscopy. We identified mEos3.2 and mMaple3 to be suitable for molecular quantification through blinking histogram analysis. We designed synthetic and genetic dimers of mEos3.2 as well as fusion proteins of monomeric and dimeric membrane proteins as reference structures, and we demonstrate their versatile use for quantitative superresolution imaging in vitro and in situ. We further found that the blinking behavior of mEos3.2 and mMaple3 is modified by a reducing agent, offering the possibility to adjust blinking parameters according to experimental needs.

scholarly journals Dense active matter model of motion patterns in confluent cell monolayers

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Silke Henkes ◽  
Kaja Kostanjevec ◽  
J. Martin Collinson ◽  
Rastko Sknepnek ◽  
Eric Bertin
Keyword(s):  
Active Matter ◽  
Motion Patterns ◽  
Cell Monolayers ◽  
Matter Model ◽  
Confluent Cell

scholarly journals Cell–cell Interaction Underlies Formation of Fluid in the Male Reproductive Tract of the Rat

2005 ◽  
Vol 125 (5) ◽  
pp. 443-454 ◽  
Author(s):  
King-ho Cheung ◽  
George P.H. Leung ◽  
Matthew C.T. Leung ◽  
Winnie W.C. Shum ◽  
Wen-liang Zhou ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Cell Types ◽  
Cell Interaction ◽  
Fluorescence Measurement ◽  
Basal Cells ◽  
Anion Secretion ◽  
Cell Monolayers ◽  
Principal Cells ◽  
Whole Cell Patch Clamp ◽  
Confluent Cell

The epithelia lining the epididymides of many species consists of several cell types. We have provided evidence that the basal cells are essential to the integrated functions of the epithelium. Basal cells, but not principal cells, and other cells in the epididymis express TRPC3 and COX-1. We have isolated basal cells from intact rat epididymis using antibody-coated Dynabeads and subjected them to whole-cell patch-clamp measurement of nonselective cation channel activity, a feature of TRPC3 protein, and Fluo-3 fluorescence measurement of intracellular Ca2+ concentration. The results show that a nonselective cation current blockable by La3+ (0.1 mM), Gd3+ (0.1 mM), or SKF96365 (20 μM) could be activated by lysylbradykinin (200 nM). In cells loaded with Fluo-3, addition of lysylbradykinin (100 nM) caused a sustained increase of intracellular Ca2+. This effect was blocked by Gd3+ (0.1 mM) or SKF96365 (20 μM) and was not observed in Fluo-3–loaded principal cells. Stimulation of basal cell/principal cell cocultures with lysylbradykinin (200 nM) evoked in principal cells a current with CFTR-Cl− channel characteristics. Isolated principal cells in the absence of basal cells did not respond to lysylbradykinin but responded to PGE2 (100 nM) with activation of a CFTR-like current. Basal cells, but not principal cells, released prostaglandin E2 when stimulated with lysylbradykinin (100 nM). The release was blocked by SKF96365 (20 μM) and BAPTA-AM (0.05 or 0.1 mM). Confluent cell monolayers harvested from a mixture of disaggregated principal cells and basal cells responded to lysylbradykinin (100 nM) and PGE2 (500 nM) with an increase in electrogenic anion secretion. The former response was dependent on prostaglandin synthesis as piroxicam blocked the response. However, cell cultures obtained from principal cells alone responded to PGE2 but not to bradykinin. These results support the notion that basal cells regulate principal cells through a Ca2+ and COX signaling pathway.

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