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Efflux pumps

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https://www.readbyqxmd.com/read/28438781/transporter-mediated-disposition-clinical-pharmacokinetics-and-cholestatic-potential-of-glyburide-and-its-primary-active-metabolites
#1
Rui Li, Yi-An Bi, Anna Vildhede, Renato J Scialis, Sumathy Mathialagan, Xin Yang, Lisa D Marroquin, Jian Lin, Manthena V S Varma
Glyburide is widely used for the treatment of type 2 diabetes mellitus. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites, M1 and M2b; and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion transporting polypeptides...
April 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28437232/epidemiological-physiological-and-molecular-characteristics-of-a-brazilian-collection-of-carbapenem-resistant-acinetobacter-baumannii-and-pseudomonas-aeruginosa
#2
Vanessa Cordeiro Dias, Juliana Alves Resende, André Netto Bastos, Lucas Quinet De Andrade Bastos, Victor Quinet De Andrade Bastos, Ricardo Villela Bastos, Cláudio Galuppo Diniz, Vânia Lúcia Da Silva
Nonfermenting Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are widespread in the environment and are increasingly associated with nosocomial infections, often associated with multidrug-resistance phenotypes. This study aimed to evaluate epidemiological, physiological, and molecular characteristics of carbapenem resistance in P. aeruginosa and A. baumannii. In total, 63 nonreplicated strains (44 A. baumannii and 19 P. aeruginosa) were isolated from hospitalized patients. Antimicrobial resistance patterns, biocide tolerance, oxidative stress, hemolytic activity, and biofilm formation were assessed...
February 24, 2017: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/28436748/disruption-of-tetr-type-regulator-aden-by-mobile-genetic-element-confers-elevated-virulence-in-acinetobacter-baumannii
#3
Rajagopalan Saranathan, Sudhakar Pagal, Ajit R Sawant, Archana Tomar, M Madhangi, Suresh Sah, Annapurna Satti, K P Arunkumar, K Prashanth
Acinetobacter baumannii is an important human pathogen and considered as a major threat due to its extreme drug resistance. In this study, the genome of a hyper-virulent MDR strain PKAB07 of A. baumannii isolated from an Indian patient was sequenced and analysed to understand its mechanisms of virulence, resistance and evolution. Comparative genomics analysis of PKAB07 revealed virulence and resistance related genes scattered throughout the genome, instead of being organized as an island, indicating the highly mosaic nature of the genome...
April 24, 2017: Virulence
https://www.readbyqxmd.com/read/28436164/synthesis-and-sar-study-of-novel-anticancer-protoflavone-derivatives-investigation-of-cytotoxicity-and-interaction-with-the-abcb1-and-abcg2-multidrug-efflux-transporters
#4
Balázs Dankó, Szilárd Tóth, Ana Martins, Vágvölgyi Máté, Norbert Kúsz, Joseph Molnár, Fang-Rong Chang, Yang-Chang Wu, Gergely Szakács, Attila Hunyadi
There is a constant need for new therapies against multidrug resistant (MDR) cancer. Natural compounds represent a promising class of novel anticancer agents. Recently, we have shown that protoflavones display activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In the present study, 52 protoflavones, including 22 new derivatives were synthesized and tested against a panel of sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics...
April 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28435070/siderophores-in-clinical-isolates-of-klebsiella-pneumoniae-promote-ciprofloxacin-resistance-by-inhibiting-the-oxidative-stress
#5
Wenli Zhang, Ying Zhang, Xinxin Wang, Fengshu Ding, Yingmei Fu, Jizi Zhao, Wuqi Song, Ogutu James Opiyo, Fengmin Zhang, Xiaobei Chen
To explore the relevance of and understand the potential mechanisms behind the production of siderophores by clinical isolates of K. pneumoniae and ciprofloxacin (CIP) resistance, we divided the K. pneumoniae isolates into two groups based on bacterial siderophores productin: high siderophore-yielding group (39 strains) and low siderophore-yielding group (38 strains). The rate of CIP resistance in K. pneumoniae (27/39 = 69.23%) from the high siderophore-yielding group was significantly higher than that (16/38 = 42...
April 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28432381/modulation-of-the-multidrug-efflux-pump-emrd-3-from-vibrio-cholerae-by-allium-sativum-extract-and-the-bioactive-agent-allyl-sulfide-plus-synergistic-enhancement-of-antimicrobial-susceptibility-by-a-sativum-extract
#6
Merissa M Bruns, Prathusha Kakarla, Jared T Floyd, Mun Mun Mukherjee, Robert C Ponce, John A Garcia, Indrika Ranaweera, Leslie M Sanford, Alberto J Hernandez, T Mark Willmon, Grace L Tolson, Manuel F Varela
The causative agent of cholera, Vibrio cholerae, is a public health concern. Multidrug-resistant V. cholerae variants may reduce chemotherapeutic efficacies of severe cholera. We previously reported that the multidrug efflux pump EmrD-3 from V. cholerae confers resistance to multiple structurally distinct antimicrobials. Medicinal plant compounds are potential candidates for EmrD-3 efflux pump modulation. The antibacterial activities of garlic Allium sativum, although poorly understood, predicts that a main bioactive component, allyl sulfide, modulates EmrD-3 efflux...
April 21, 2017: Archives of Microbiology
https://www.readbyqxmd.com/read/28428443/mechanisms-of-pinometostat-epz-5676-treatment-emergent-resistance-in-mll-rearranged-leukemia
#7
Carly T Campbell, Jessica N Haladyna, David A Drubin, Ty M Thomson, Michael J Maria, Taylor Yamauchi, Nigel J Waters, Edward J Olhava, Roy M Pollock, Jesse J Smith, Robert A Copeland, Stephen J Blakemore, Kathrin M Bernt, Scott R Daigle
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well characterized leukemic genes.  Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment emergent resistance (TER) in cell lines confirmed to have MLL-r...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28428424/biased-partitioning-of-the-multidrug-efflux-pump-acrab-tolc-underlies-long-lived-phenotypic-heterogeneity
#8
Tobias Bergmiller, Anna M C Andersson, Kathrin Tomasek, Enrique Balleza, Daniel J Kiviet, Robert Hauschild, Gašper Tkačik, Călin C Guet
The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood. We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations...
April 21, 2017: Science
https://www.readbyqxmd.com/read/28427190/pygopus2-inhibits-the-efficacy-of-paclitaxel-induced-apoptosis-and-induces-multidrug-resistance-in-human-glioma-cells
#9
Cefan Zhou, Hongxia Cheng, Wenying Qin, Yi Zhang, Hui Xiong, Jing Yang, Huang Huang, Yefu Wang, Xing-Zhen Chen, Jingfeng Tang
Anti-microtubule drugs, such as paclitaxel (PTX), are extensively used for the treatment of numerous cancers. However, growing evidence has shown that PTX resistance, either intrinsic or acquired, frequently occurs in patients and results in the failure of treatment, contributing to the high cancer mortality rate. Therefore, it is necessary to identify the genes or pathways involved in anti-microtubule drug resistance for future successful treatment of cancers. Pygopus2 (Pygo2), which contains a Zn-coordinated plant homeodomain (PHD) finger domain, is critical for β-catenin-dependent transcriptional switches in normal and malignant tissues and is over-expressed in various cancers, including human brain glioma...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425875/occurrence-of-qnrb1-and-qnrb12-genes-mutation-in-gyra-and-ramr-and-expression-of-efflux-pumps-in-isolates-of-klebsiella-pneumoniae-carriers-of-blakpc-2
#10
Alexsandra Maria Lima Scavuzzi, Maria Amélia Vieira Maciel, Heloísa Ramos Lacerda de Melo, Luiz Carlos Alves, Fábio André Brayner, Ana Catarina Souza Lopes
PURPOSE: The occurrence of quinolone-resistance genes (qnrA, qnrB and qnrS), the presence of mutations in gyrA, gyrB and parC, as well as the expression of efflux pumps (acrB and acrF) and mutations in the gene ramR. METHODOLOGY: Were investigated in 30 blaKPC-2-positive isolates of Klebsiella pneumoniae taken from infection and colonization in hospital patients from Recife-PE, Brazil. The detection of the qnr, acrB and acrF genes and analysis of the mutations in ramR and the quinolone-resistance-determining regions of gyrA, gyrB and parC were performed by PCR followed by DNA sequencing...
April 21, 2017: Journal of Medical Microbiology
https://www.readbyqxmd.com/read/28425219/resistance-modifying-activity-in-vinblastine-resistant-human-breast-cancer-cells-by-oligosaccharides-obtained-from-mucilage-of-chia-seeds-salvia-hispanica
#11
Daniel G Rosas-Ramírez, Mabel Fragoso-Serrano, Sonia Escandón-Rivera, Alba L Vargas-Ramírez, Juan P Reyes-Grajeda, Manuel Soriano-García
The multidrug resistance (MDR) phenotype is considered as a major cause of the failure in cancer chemotherapy. The acquisition of MDR is usually mediated by the overexpression of drug efflux pumps of a P-glycoprotein. The development of compounds that mitigate the MDR phenotype by modulating the activity of these transport proteins is an important yet elusive target. Here, we screened the saponification and enzymatic degradation products from Salvia hispanica seed's mucilage to discover modulating compounds of the acquired resistance to chemotherapeutic in breast cancer cells...
April 20, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28419231/antibiotic-resistance-in-staphylococcus-aureus-current-status-and-future-prospects
#12
Timothy J Foster
The major targets for antibiotics in staphylococci are (i) the cell envelope, (ii) the ribosome and (iii) nucleic acids. Several novel targets emerged from recent targeted drug discovery programmes including the ClpP protease and FtsZ from the cell division machinery. Resistance can either develop by horizontal transfer of resistance determinants encoded by mobile genetic elements viz plasmids, transposons and the staphylococcal cassette chromosome or by mutations in chromosomal genes. Horizontally acquired resistance can occur by one of the following mechanisms: (i) enzymatic drug modification and inactivation, (ii) enzymatic modification of the drug binding site, (iii) drug efflux, (iv) bypass mechanisms involving acquisition of a novel drug-resistant target, (v) displacement of the drug to protect the target...
April 13, 2017: FEMS Microbiology Reviews
https://www.readbyqxmd.com/read/28417918/high-prevalence-of-blandm-1-blavim-qace-and-qace%C3%AE-1-genes-and-their-association-with-decreased-susceptibility-to-antibiotics-and-common-hospital-biocides-in-clinical-isolates-of-acinetobacter-baumannii
#13
Fatma Alzahraa M Gomaa, Zeinab H Helal, Mazhar I Khan
The objective of this study was to evaluate the susceptibility of metallo-β-lactamase (MBL)-producing Acinetobacter baumannii (A. baumannii) clinical isolates to biocides. We also determined the prevalence and correlation of efflux pump genes, class 1 integron and MBL encoding genes. In addition, blaVIM, blaNDM-1, qacE and qacEΔ1 nucleotide sequence analysis was performed and compared to sequences retrieved from GenBank at the National Center for Biotechnology Information database. A. baumannii had a resistance rate to carbapenem of 71...
April 12, 2017: Microorganisms
https://www.readbyqxmd.com/read/28417533/split-tasks-of-asymmetric-nucleotide-binding-sites-in-the-heterodimeric-abc-exporter-efrcd
#14
Lea M Hürlimann, Michael Hohl, Markus A Seeger
Many heterodimeric ATP-binding cassette (ABC) exporters evolved asymmetric ATP-binding sites containing a degenerate site incapable of ATP hydrolysis due to noncanonical substitutions in conserved sequence motifs. Recent studies revealed that nucleotide binding to the degenerate site stabilizes contacts between the nucleotide-binding domains (NBDs) of the inward-facing transporter and regulates ATP hydrolysis at the consensus site via allosteric coupling mediated by the D-loops. However, it is unclear whether nucleotide binding to the degenerate site is strictly required for substrate transport...
April 18, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28416660/redefining-the-essential-trafficking-pathway-for-outer-membrane-lipoproteins
#15
Marcin Grabowicz, Thomas J Silhavy
The outer membrane (OM) of Gram-negative bacteria is a permeability barrier and an intrinsic antibiotic resistance factor. Lipoproteins are OM components that function in cell wall synthesis, diverse secretion systems, and antibiotic efflux pumps. Moreover, each of the essential OM machines that assemble the barrier requires one or more lipoproteins. This dependence is thought to explain the essentiality of the periplasmic chaperone LolA and its OM receptor LolB that traffic lipoproteins to the OM. However, we show that in strains lacking substrates that are toxic when mislocalized, both LolA and LolB can be completely bypassed by activating an envelope stress response without compromising trafficking of essential lipoproteins...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416541/efflux-attenuates-the-anti-bacterial-activity-of-q203-in-mycobacterium-tuberculosis
#16
Jichan Jang, Ryangyeo Kim, Minjeong Woo, Jinsun Jeong, Da Eun Park, Guehye Kim, Vincent Delorme
New and improved treatments for tuberculosis (TB) are urgently needed. Recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available anti-tuberculosis agents. The aim of this study was to evaluate the effectiveness of verapamil in combination with the anti-tuberculosis drug candidate Q203, which has recently been developed and is currently under clinical trials as a potential anti-tuberculosis agent...
April 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28413506/active-efflux-pump-adeb-is-involved-in-multidrug-resistance-of-acinetobacter-baumannii-induced-by-antibacterial-agents
#17
Tingting Zhang, Min Wang, Yixin Xie, Xianping Li, Zhihui Dong, Yanhua Liu, Ling Wang, Min Yang, Huan Song, Hong Cao, Wei Cao
The aim of the present study was to investigate the resistance of Acinetobacter baumannii, which was induced by cefepime (FEP), cefoperazone-sulbactam (SCF), tazobactam (TZP), levofloxacin (LEV), amikacin (AK), imipenem (IPM), and ciprofloxacin (CIP), in vitro. Multi-step drug resistance selection of 16 A. baumannii strains was performed using seven antibacterial agents (FEP, TZP, CIP, AK, IPM, SCF, and LEV). The minimum inhibitory concentration (MIC) was determined using the agar dilution method. Random amplified polymorphic DNA polymerase chain reaction was performed to analyze the genotypes and the carrying rates of aac(3)-I, aac(6')-I, ant(3)-I, aph(3)-Via, OXA-23, OXA-24, AmpC, TEM-1, metallo-β-lactamase gene (IMP), armA, rmtA, rmtB, parC, gyrA and adeB...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28411377/mir-495-sensitizes-mdr-cancer-cells-to-the-combination-of-doxorubicin-and-taxol-by-inhibiting-mdr1-expression
#18
Zhenyou Zou, Ruyi Zou, Dan Zong, Yonghong Shi, Jinyao Chen, Jie Huang, Jiahui Zhu, Liguan Chen, Xiaoyan Bao, Yuan Liu, Weihao Liu, Wenhui Huang, Jingsang Hu, Zhi Chen, Xiaojie Lao, Chaoqun Chen, Xiaoli Huang, Yao Lu, Xueyin Ni, Daoquan Fang, Dengqiang Wu, Shuangshuang Lu, Mingzhu Jiang, Chenyang Qiu, Yuya Wu, Qisha Qiu, Yanyuan Dong, Yangyang Su, Chenmin Zhao, Zhihe Zhong, Jing Cai, Yong Liang
MDR1 is highly expressed in MDR A2780DX5 ovarian cancer cells, MDR SGC7901R gastric cancer cells and recurrent tumours. It pumps cytoplasmic agents out of cells, leading to decreased drug accumulation in cells and making cancer cells susceptible to multidrug resistance. Here, we identified that miR-495 was predicted to target ABCB1, which encodes protein MDR1. To reduce the drug efflux and reverse MDR in cancer cells, we overexpressed a miR-495 mimic in SGC7901R and A2780DX cells and in transplanted MDR ovarian tumours in vivo...
April 14, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28409644/amphiphilic-tobramycin-lysine-conjugates-sensitize-multidrug-resistant-gram-negative-bacteria-to-rifampicin-and-minocycline
#19
Yinfeng Lyu, Xuan Yang, Sudeep Goswami, Bala Kishan Gorityala, Temilolu Idowu, Ronald Domalaon, George G Zhanel, Anshan Shan, Frank Schweizer
Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28408143/tetrandrine-potentiates-the-glucocorticoid-pharmacodynamics-via-inhibiting-p-glycoprotein-and-mitogen-activated-protein-kinase-in-mitogen-activated-human-peripheral-blood-mononuclear-cells
#20
Wencheng Xu, Kehan Meng, Yuanchao Tu, Sachiko Tanaka, Kenji Onda, Kentaro Sugiyama, Toshihiko Hirano, Haruki Yamada
Glucocorticoids play significant roles in treatments of inflammatory and autoimmune diseases. Some patients show a poor or absent response even to high doses of glucocorticoids. The purpose of this study was to explore whether tetrandrine combined with glucocorticoids could be a new treatment strategy to resolve glucocorticoids resistance. Information on glucocorticoids sensitivity was usually obtained through mitogen-activated human peripheral blood mononuclear cells in cell culture procedures. Thus, human peripheral blood mononuclear cells was chosen as a model to study the immunosuppressive effect of methylprednisolone combined with tetrandrine, including the possible action mechanisms...
April 10, 2017: European Journal of Pharmacology
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