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efflux pump inhibition

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https://www.readbyqxmd.com/read/29318976/algerian-propolis-potentiates-doxorubicin-mediated-anticancer-effect-against-human-pancreatic-panc-1-cancer-cell-line-through-cell-cycle-arrest-apoptosis-induction-and-p-glycoprotein-inhibition
#1
Hassiba Rouibah, Lahouel Mesbah, Wided Kebsa, Malek Zihlif, Mamoun Ahram, Bachaer Aburmeleih, Ibtihal Mostafa, Hemzeh El Amir
BACKGROUND: Pancreatic cancer is one of the most aggressive and lethal cancer, with poor prognosis and high resistant to current chemotherapeutic agents. Therefore, new therapeutic strategies and targets are underscored. Propolis has been reported to exhibit a broad spectrum of biological activities including anticancer activity. OBJECTIVE: This study was carried out to assess the possible efficacy of Algerian propolis on the antitumor effect of doxorubicin on human pancreatic cancer cell line (PANC-1)...
January 10, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29280358/thermoresponsive-supramolecular-chemotherapy-by-v-shaped-armed-%C3%AE-cyclodextrin-star-polymer-to-overcome-drug-resistance
#2
Xiaoshan Fan, Hongwei Cheng, Xiaoyuan Wang, Enyi Ye, Xian Jun Loh, Yun-Long Wu, Zibiao Li
Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer β-CD-v-(PEG-β-PNIPAAm)7 consisting of a β-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between β-cyclodextrin and anti-cancer drug via inclusion complex (IC)...
December 27, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/29275225/the-efflux-pump-inhibitor-phenylalanine-arginine-beta-naphthylamide-pa%C3%AE-n-increases-the-resistance-to-carbapenems-in-chilean-clinical-isolates-of-kpc-producing-k-pneumoniae
#3
Alejandra Vera-Leiva, Sergio Carrasco-Anabalón, Celia A Lima, Nicolás Villagra, Mariana Domínguez, Helia Bello-Toledo, Gerardo González-Rocha
OBJECTIVES: KPC-producing strains present a wide range of MICs of carbapenems; this variation may be due to different gene expression levels of the blaKPC and porin genes, associated with efflux-pumps and the production of ESBLs and/or AmpC β-lactamase. The aim of this study was to determine the role of efflux-pumps inhibited by PAβN in the resistance to carbapenems in Chilean clinical isolates of K. pneumoniae harbouring the gene blaKPC. METHODS: Minimum Inhibitory Concentration (MIC) was determined by the agar dilution method for imipenem, meropenem, ertapenem and ciprofloxacin in the presence and absence of PAβN (25mg/L)...
December 21, 2017: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29246313/assessment-of-the-drug-interaction-potential-of-unconjugated-and-galnac3-conjugated-2-moe-asos
#4
Colby S Shemesh, Rosie Z Yu, Mark S Warren, Michael Liu, Mirza Jahic, Brandon Nichols, Noah Post, Song Lin, Daniel A Norris, Eunju Hurh, Jane Huang, Tanya Watanabe, Scott P Henry, Yanfeng Wang
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored...
December 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29246087/in-silico-interaction-studies-suggest-rnd-efflux-pump-mediates-polymyxin-resistance-in-acinetobacter-baumannii
#5
Privita Verma, Pramila Maurya, Monalisa Tiwari, Vishvanath Tiwari
Bacterial efflux pumps have emerged as antibiotic resistance determinants and confers multi-drug resistance to a broad range of antimicrobials as well as non-antibiotic substances. A study about translocation of antibiotic molecules through the efflux transporter, will contribute in determining substrate specificity. In the present study, we have explored RND family efflux pump extensively found in Acinetobacter baumannii i.e. AdeABC. Besides, another well studied RND efflux pump, AcrAB-TolC together with a non-RND efflux pump, NorM were investigated for comparative analysis...
December 15, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29243909/optimization-of-coad-inhibitors-against-gram-negative-organisms-through-targeted-metabolomics
#6
Christopher M Rath, Bret M Benton, Javier de Vicente, Joseph E Drumm, Mei Geng, Cindy Li, Robert J Moreau, Xiaoyu Shen, Colin K Skepper, Micah Steffek, Kenneth Takeoka, Lisha Wang, Jun-Rong Wei, Wenjian Xu, Qiong Zhang, Brian Y Feng
Drug-resistant Gram-negative bacteria are of increasing concern worldwide. Novel antibiotics are needed, but their development is complicated by the requirement to simultaneously optimize molecules for target affinity and cellular potency, which can result in divergent structure-activity relationships (SARs). These challenges were exemplified during our attempts to optimize inhibitors of the bacterial enzyme CoaD originally identified through a biochemical screen. To facilitate lead optimization, we developed mass spectroscopy assays based on the hypothesis that levels of CoA metabolites would reflect the cellular enzymatic activity of CoaD...
December 22, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29239018/design-synthesis-and-biological-evaluation-of-1-ethyl-3-thiazol-2-yl-urea-derivatives-as-escherichia-coli-dna-gyrase-inhibitors
#7
Tihomir Tomašič, Michaela Barančoková, Nace Zidar, Janez Ilaš, Päivi Tammela, Danijel Kikelj
Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2,6-diamine, 2-(2-aminothiazol-4-yl)acetic acid, and benzo[1,2-d]thiazole-2,6-diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo[1,2-d]thiazoles 32-34, 36, and 37 with IC50 values in the low micromolar range...
December 14, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29238994/intestinal-p-glycoprotein-inhibitors-benzoxanthone-analogues
#8
Song Wha Chae, Jaeok Lee, Jung Hyun Park, Youngjoo Kwon, Younghwa Na, Hwa Jeong Lee
OBJECTIVES: The inhibitors of P-glycoprotein (P-gp) which limits an access of exogenous compounds in the luminal membrane of the intestine have been studied to enhance the intestinal P-gp-mediated absorption of anticancer drugs. METHODS: Inhibition of the efflux pump by synthesized benzoxanthone derivatives was investigated in vitro and in vivo. MCF-7/ADR cell line was used for cytotoxicity assay and [3 H]-daunomycin (DNM) accumulation/efflux study. Eight benzoxanthone analogues were tested for their effects on DNM cytotoxicity...
December 13, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29238700/requirement-for-ergosterol-in-berberine-tolerance-underlies-synergism-of-fluconazole-and-berberine-against-fluconazole-resistant-candida-albicans-isolates
#9
Yi Xu, Hua Quan, Yan Wang, Hua Zhong, Jun Sun, Jianjiang Xu, Nuan Jia, Yuanying Jiang
Candida albicans is one of the most common fungal pathogens. Our previous study demonstrated that concomitant use of berberine (BBR) and fluconazole (FLC) showed a synergistic action against FLC-resistant C. albicans in vitro and BBR had a major antifungal effect in the synergism, while FLC played a role of increasing the intracellular BBR concentration. Since the antifungal activity of BBR alone is very weak (MIC > 128 μg/mL), it was assumed that FLC-resistant C. albicans was naturally tolerant to BBR, and this tolerance could be reversed by FLC...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29236925/increased-thiol-levels-in-antimony-resistant-leishmania-infantum-isolated-from-treatment-refractory-visceral-leishmaniasis-in-brazil
#10
Lucas S Magalhães, Lays Gs Bomfim, Sthefanne G Mota, Geydson S Cruz, Cristiane B Corrêa, Diego M Tanajura, Michael W Lipscomb, Valéria M Borges, Amélia R de Jesus, Roque P de Almeida, Tatiana R de Moura
BACKGROUND Treatment-refractory visceral leishmaniasis (VL) has become an important problem in many countries. OBJECTIVES We evaluated the antimony-resistance mechanisms of Leishmania infantum isolated from VL patients refractory or responsive to treatment with pentavalent antimony. METHODS Strains isolated from antimony-refractory patients (in vitro antimony-resistant isolates) and antimony-responsive patients (in vitro antimony-sensitive isolates) were examined. Morphological changes were evaluated by transmission electron microscopy after trivalent antimony exposure...
February 2018: Memórias do Instituto Oswaldo Cruz
https://www.readbyqxmd.com/read/29220791/design-synthesis-and-biological-activity-evaluation-of-novel-4-subtituted-2-naphthamide-derivatives-as-acrb-inhibitors
#11
Yinhu Wang, Rumana Mowla, Shengli Ji, Liwei Guo, Miguel A De Barros Lopes, Chaobin Jin, Di Song, Shutao Ma, Henrietta Venter
A novel series of 4-substituted 2-naphthamide derivatives were designed, synthesized and evaluated for their biological activity. In particular, the ability of the compounds to potentiate the action of antibiotics, to inhibit Nile Red efflux and to target AcrB specifically was investigated. The results indicated that most of the 4-substituted 2-naphthamide derivatives were able to synergize with the antibiotics tested, and inhibit Nile Red efflux by AcrB in the resistant phenotype. Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs)...
December 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29211738/metformin-inhibits-the-development-and-promotes-the-resensitization-of-treatment-resistant-breast-cancer
#12
Gerald Davies, Liubov Lobanova, Wojciech Dawicki, Gary Groot, John R Gordon, Matthew Bowen, Troy Harkness, Terra Arnason
Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors...
2017: PloS One
https://www.readbyqxmd.com/read/29210342/antibiotics-potentiating-potential-of-catharanthine-against-superbug-pseudomonas-aeruginosa
#13
Gaurav Raj Dwivedi, Rekha Tyagi, Sanchita Gupta, Shubhandra Tripathi, Sanghamitra Pati, Santosh K Srivastava, Mahendra P Darokar, Ashok Sharma
Multidrug resistance (MDR) put an alarming situation like preantibiotic era which compels us to invigorate the basic science of anti-infective chemotherapy. Hence the drug resistant genes/proteins were explored as promising drug targets. Keeping this thing in mind, proteome of Pseudomonas aeruginosa PA01 was explored, which resulted in the identification of tripartite protein complexes (MexA, MexB and OprM) as promising drug target for the screening of natural and synthetic inhibitors. The purpose of present investigation was to explore the drug resistance reversal potential mechanism of catharanthine isolated from the leaves of Catharanthus roseous...
December 6, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29208281/overcoming-stc2-mediated-drug-resistance-through-drug-and-gene-co-delivery-by-phb-pdmaema-cationic-polyester-in-liver-cancer-cells
#14
Hongwei Cheng, Zhixian Wu, Caisheng Wu, Xiaoyuan Wang, Sing Shy Liow, Zibiao Li, Yun-Long Wu
Stanniocalcin 2 (STC2) overexpression in hepatocellular carcinoma (HCC) could lead to poor prognosis, which might be due to its induced P-glycoprotein and Bcl-2 protein expression level increase. P-glycoprotein or membrane pump induced drug efflux and altered prosurvival Bcl-2 expression are key mechanisms for drug resistance leading to failure of chemotherapy in HCC. However, current strategy to overcome both P-glycoprotein and Bcl-2 protein induced drug resistance was rarely reported. In this work, we utilized an amphiphilic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) cationic polyester to encapsulate chemotherapeutic paclitaxel (PTX) in hydrophobic PHB domain and Bcl-2 convertor Nur77/ΔDBD gene (Nur77 without DNA binding domain for mitochondria localization) by formation of polyplex due to cationic PDMAEMA segment, to effectively inhibit the drug resistant HepG2/STC2 and SMCC7721/STC2 liver cancer cell growth...
February 1, 2018: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/29206128/conformational-study-of-z-5-4-chlorobenzylidene-2-4-2-hydroxyethyl-piperazin-1-yl-3h-imidazol-4-5h-one-in-different-environments-insight-into-the-structural-properties-of-bacterial-efflux-pump-inhibitors
#15
Ewa Żesławska, Wojciech Nitek, Jadwiga Handzlik
The 2-amine derivatives of 5-arylidene-3H-imidazol-4(5H)-one are a new class of bacterial efflux pump inhibitors, the chemical compounds that are able to restore antibiotic efficacy against multidrug resistant bacteria. 5-Arylidene-3H-imidazol-4(5H)-ones with a piperazine ring at position 2 reverse the mechanisms of multidrug resistance (MDR) of the particularly dangerous Gram-negative bacteria E. coli by inhibition of the efflux pump AcrA/AcrB/TolC (a main multidrug resistance mechanism in Gram-negative bacteria, consisting of a membrane fusion protein, AcrA, a Resistant-Nodulation-Division protein, AcrB, and an outer membrane factor, TolC)...
December 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
https://www.readbyqxmd.com/read/29186665/discovery-and-characterization-of-chemical-compounds-that-inhibit-the-function-of-aspartyl-trna-synthetase-from-pseudomonas-aeruginosa
#16
Araceli Corona, Stephanie O Palmer, Regina Zamacona, Benjamin Mendez, Frank B Dean, James M Bullard
Pseudomonas aeruginosa, an opportunistic pathogen, is highly susceptible to developing resistance to multiple antibiotics. The gene encoding aspartyl-tRNA synthetase (AspRS) from P. aeruginosa was cloned and the resulting protein characterized. AspRS was kinetically evaluated, and the KM values for aspartic acid, ATP, and tRNA were 170, 495, and 0.5 μM, respectively. AspRS was developed into a screening platform using scintillation proximity assay (SPA) technology and used to screen 1690 chemical compounds, resulting in the identification of two inhibitory compounds, BT02A02 and BT02C05...
November 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29180476/a-potent-metabolically-stable-tubulin-inhibitor-targets-the-colchicine-binding-site-and-overcomes-taxane-resistance
#17
Kinsie E Arnst, Yuxi Wang, Dong-Jin Hwang, Yi Xue, Terry Costello, David Hamilton, Qiang Chen, Jinliang Yang, Frank Park, James T Dalton, Duane D Miller, Wei Li
Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29177837/high-throughput-flow-cytometry-screening-of-multidrug-efflux-systems
#18
Mark K Haynes, Matthew Garcia, Ryan Peters, Anna Waller, Pietro Tedesco, Oleg Ursu, Cristian G Bologa, Radleigh G Santos, Clemencia Pinilla, Terry H Wu, Julie A Lovchik, Tudor I Oprea, Larry A Sklar, George P Tegos
The resistance nodulation cell division (RND) family of proteins are inner membrane transporters that associate with periplasmic adaptor proteins and outer membrane porins to affect substrate transport from the cytosol and periplasm in Gram-negative bacteria. Various structurally diverse compounds are substrates of RND transporters. Along with their notable role in antibiotic resistance, these transporters are essential for niche colonization, quorum sensing, and virulence as well as for the removal of fatty acids and bile salts...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29177832/molecular-modeling-of-multidrug-properties-of-resistance-nodulation-division-rnd-transporters
#19
Pierpaolo Cacciotto, Venkata K Ramaswamy, Giuliano Malloci, Paolo Ruggerone, Attilio V Vargiu
Efflux pumps of the resistance nodulation division (RND) superfamily are among the major contributors to intrinsic and acquired multidrug resistance in Gram-negative bacteria. Structural information on AcrAB-TolC and MexAB-OprM, major efflux pumps of Escherichia coli and Pseudomonas aeruginosa respectively, boosted intensive research aimed at understanding the molecular mechanisms ruling the active extrusion processes. In particular, several studies were devoted to the understanding of the determinants behind the extraordinary broad specificity of the RND transporters AcrB and MexB...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29173059/mannosylated-thiolated-polyethylenimine-nanoparticles-for-the-enhanced-efficacy-of-antimonial-drug-against-leishmaniasis
#20
Hafiz S Sarwar, Sehreen Ashraf, Sohail Akhtar, Muhammad F Sohail, Syed Z Hussain, Muhammad Rafay, Masoom Yasinzai, Irshad Hussain, Gul Shahnaz
AIM: Our aim was to inhibit trypanothione reductase (TR) and P-gp efflux pump of Leishmania by the use of thiolated polymers. Thus, increasing the intracellular accumulation and therapeutic effectiveness of antimonial compounds. METHODS: Mannosylated thiolated chitosan and mannosylated thiolated chitosan-polyethyleneimine graft were synthesized and characterized. Meglumine antimoniate-loaded nanoparticles were prepared and evaluated for TR and P-gp efflux pump inhibition, biocompatibility, macrophage uptake and antileishmanial potential...
November 27, 2017: Nanomedicine
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