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efflux pump inhibition

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https://www.readbyqxmd.com/read/28623111/reversal-of-abcb1-mediated-efflux-by-imatinib-and-nilotinib-in-cells-expressing-various-transporter-levels
#1
Petr Mlejnek, Petr Kosztyu, Petr Dolezel, Susan E Bates, Eliska Ruzickova
Recently, it has been suggested that imatinib (IM) and nilotinib (NIL) could be studied beyond their original application, as inhibitors of the drug efflux pump ABCB1 (P-glycoprotein, MDR1). Since the reversal of ABCB1-mediated resistance has never been successfully demonstrated in the clinic, we addressed the question of whether IM and NIL may actually serve as efficient inhibitors of ABCB1. Here we define an efficient inhibitor as a compound that achieves full (90-100%) reversal of drug efflux at a concentration that does not exhibit significant off-target toxicity in vitro...
June 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28621579/optimization-of-antimicrobial-photodynamic-therapy-in-biofilms-by-inhibiting-efflux-pump
#2
Tatiana Maria Starck Fogaça de Aguiar Coletti, Laura Marise de Freitas, Ana Marisa Fusco Almeida, Carla Raquel Fontana
BACKGROUND: One of the main mechanisms of microbial resistance is given by efflux pumps, which reduce the effectiveness of antimicrobials by decreasing their intracellular concentration. OBJECTIVE AND METHODS: Considering that efflux pump inhibitors are promising adjuvant molecules for antibiotics in infections, in this study, using XTT test and colony forming unit (CFU) counting, we evaluated the association between the pump inhibitor verapamil (VP) and the antimicrobial photodynamic therapy (aPDT) mediated by methylene blue (MB) in biofilms of Escherichia coli and Staphylococcus aureus to optimize the bacterial reduction...
June 15, 2017: Photomedicine and Laser Surgery
https://www.readbyqxmd.com/read/28618136/amphiphilic-cargo-loaded-nanocarrier-enhances-antibiotic-uptake-and-perturbs-efflux-effective-synergy-for-mitigation-of-methicillin-resistant-staphylococcus-aureus
#3
Durairaj Thiyagarajan, Gopal Das, Ramesh Aiyagari
A pyridinium amphiphile-loaded Poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC could render 8 × and 6 × reduction of the minimum biofilm eradication concentration (MBEC90) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in case of gentamicin, C1-PNC promoted enhanced cellular uptake of the antibiotic, while the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin leading to effective killing of MRSA cells...
June 15, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28606508/tumor-specific-delivery-of-doxorubicin-through-conjugation-of-ph-responsive-peptide-for-overcoming-drug-resistance-in-cancer
#4
Chunlai Feng, Mengjie Rui, Haijun Shen, Yuanrong Xin, Jie Zhang, Jun Li, Lixiang Yue, Wenlong Lai, Ximing Xu
The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior...
June 9, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28600147/chemoresistance-and-chemosensitization-in-cholangiocarcinoma
#5
REVIEW
Jose J G Marin, Elisa Lozano, Elisa Herraez, Maitane Asensio, Silvia Di Giacomo, Marta R Romero, Oscar Briz, Maria A Serrano, Thomas Efferth, Rocio I R Macias
One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined...
June 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28597653/overexpression-of-atp-binding-cassette-subfamily-g-member-2-confers-resistance-to-phosphatidylinositol-3-kinase-inhibitor-pf-4989216-in-cancer-cells
#6
Chung-Pu Wu, Megumi Murakami, Sung-Han Hsiao, An-Wei Chou, Yan-Qing Li, Yang-Hui Huang, Tai-Ho Hung, Suresh V Ambudkar
Deregulated activation of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently found in human cancers, which plays a key role in promoting cancer proliferation and resistance to anticancer therapies. Therefore, developing inhibitors targeting key components of the PI3K/Akt/mTOR signaling pathway has great clinical significance. PF-4989216 is a novel, orally available small-molecule drug that was developed to selectively inhibit the PI3K/Akt/mTOR signaling pathway and subsequent cancer cell proliferation...
June 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28570601/characterization-of-2-2-nitro-4-trifluoromethylbenzoyl-1-3-cyclohexanedione-resistance-in-pyomelanogenic-pseudomonas-aeruginosa-dkn343
#7
Laura M Ketelboeter, Sonia L Bardy
Pyomelanin is a reddish-brown pigment that provides bacteria and fungi protection from oxidative stress, and is reported to contribute to infection persistence. Production of this pigment can be inhibited by the anti-virulence agent 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). The Pseudomonas aeruginosa clinical isolate DKN343 exhibited high levels of resistance to NTBC, and the mechanism of pyomelanin production in this strain was uncharacterized. We determined that pyomelanin production in the clinical Pseudomonas aeruginosa isolate DKN343 was due to a loss of function in homogentisate 1,2-dioxygenase (HmgA)...
2017: PloS One
https://www.readbyqxmd.com/read/28565825/a-comparison-of-adeb-gene-expression-levels-under-conditions-of-induced-resistance-by-different-drugs-in-vitro-in-acinetobacter-baumannii
#8
Wan Zhu, Hui Wang, Jing-Ping Zhang
The present study was designed to analyze the difference of the adeB gene expression levels under conditions of induced resistance and to verify the significance of the AdeABC efflux pump in the in vitro induction of Acinetobacter baumannii (A. baumannii). Strains were isolated from blood or drainage samples in the First Hospital of China Medical University. The minimum inhibitory concentration (MIC) was determined by a broth microdilution method. In addition, an in vitro induction of drug-resistance tests was confirmed with the three drugs...
May 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28552691/identification-of-bile-acids-responsible-for-inhibiting-the-bile-salt-export-pump-leading-to-bile-acid-accumulation-and-cell-toxicity-in-rat-hepatocytes
#9
Kumiko Oizumi, Shuichi Sekine, Meiko Fukagai, Takeshi Susukida, Kousei Ito
Inhibition of bile salt export pump (BSEP) causes hepatic accumulation of toxic bile acid (BA), leading to hepatocyte death. We reported a sandwich-cultured hepatocyte (SCH)-based model that can estimate potential cholestatic-compounds by assessing their ability to induce hepatotoxicity in combination with a titrated amount of human 12 BA-species. However, there is little information about the specific BA(s) responsible for hepatotoxicity, when BSEP is inhibited. This study measured the accumulation of each BA in rat SCHs in the presence of 10μM cyclosporine A (CsA), which only inhibits BSEP, and 50μM CsA, which further inhibits basolateral BA efflux transporters...
May 25, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28549490/whole-genome-analysis-reveals-new-insights-into-macrolide-resistance-in-mycoplasma-pneumoniae
#10
Shao Li Li, Hong Mei Sun, Bao Li Zhu, Fei Liu, Han Qing Zhao
OBJECTIVE: Mutations in 23S rRNA gene are known to be associated with macrolide resistance in Mycoplasma pneumoniae (M. pneumoniae). However, these mutations alone do not fully explain the high resistance rates in Asia. The aim of this study was to investigate other possible mutations involved in macrolide resistance in M. pneumoniae. METHODS: The whole genomes of 10 clinical isolates of M. pneumoniae with macrolide resistance were sequenced by Illumina HiSeq2000 platform...
May 2017: Biomedical and Environmental Sciences: BES
https://www.readbyqxmd.com/read/28533185/the-small-molecule-iitr08027-restores-the-antibacterial-activity-of-fluoroquinolones-against-multidrug-resistant-acinetobacter-baumannii-by-efflux-inhibition
#11
Tapas Bhattacharyya, Atin Sharma, Jawed Akhter, Ranjana Pathania
Efflux pumps are one of the major determinants of multiple drug resistance. In this study, AbeM, a multidrug efflux pump in Acinetobacter baumannii, was cloned into a multicopy plasmid (pUC18) and was transformed into an efflux-deficient mutant of Escherichia coli (KAM32). The elevated resistance profile of the recombinant E. coli for ciprofloxacin was utilised to screen a small-molecule library of 8000 molecules to identify IITR08027, a small molecule that is not inhibitory on its own but that could potentiate the activity of ciprofloxacin...
May 19, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28516003/mode-of-action-of-the-2-phenylquinoline-efflux-inhibitor-pqq4r-against-escherichia-coli
#12
Diana Machado, Laura Fernandes, Sofia S Costa, Rolando Cannalire, Giuseppe Manfroni, Oriana Tabarrini, Isabel Couto, Stefano Sabatini, Miguel Viveiros
Efflux pump inhibitors are of great interest since their use as adjuvants of bacterial chemotherapy can increase the intracellular concentrations of the antibiotics and assist in the battle against the rising of antibiotic-resistant bacteria. In this work, we have described the mode of action of the 2-phenylquinoline efflux inhibitor (4-(2-(piperazin-1-yl)ethoxy)-2-(4-propoxyphenyl) quinolone - PQQ4R), against Escherichia coli, by studding its efflux inhibitory ability, its synergistic activity in combination with antibiotics, and compared its effects with the inhibitors phenyl-arginine-β-naphthylamide (PAβN) and chlorpromazine (CPZ)...
2017: PeerJ
https://www.readbyqxmd.com/read/28506804/chloroquine-enhances-the-antimycobacterial-activity-of-isoniazid-and-pyrazinamide-by-reversing-inflammation-induced-macrophage-efflux
#13
U Matt, P Selchow, M Dal Molin, S Strommer, O Sharif, K Schilcher, F Andreoni, A Stenzinger, A S Zinkernagel, M Zeitlinger, P Sander, J Nemeth
Mycobacterium tuberculosis (MTB) is notorious for persisting within host macrophages. Efflux pumps decrease intracellular drug levels, thus fostering persistence of MTB during therapy. Isoniazid (INH) and pyrazinamide (PZA) are substrates of the efflux pump breast cancer resistance protein-1 (BCRP-1), which is inhibited by chloroquine (CQ). In this study, BCRP-1 was found to be expressed on macrophages of human origin and on foamy giant cells at the site of MTB infection. In the current in vitro study, interferon-gamma (IFNγ) increased the expression of BCRP-1 in macrophages derived from the human monocytic leukaemia cell line THP-1...
May 12, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28504927/mechanisms-of-quinolone-action-and-resistance-where-do-we-stand
#14
REVIEW
Susana Correia, Patrícia Poeta, Michel Hébraud, José Luis Capelo, Gilberto Igrejas
Quinolone antibiotics represent one of the most important classes of anti-infective agents and, although still clinically valuable, their use has been compromised by the increasing emergence of resistant strains, which has become a prevalent clinical problem. Quinolones act by inhibiting the activity of DNA gyrase and topoisomerase IV - two essential bacterial enzymes that modulate the chromosomal supercoiling required for critical nucleic acid processes. The acquisition of quinolone resistance is recognized to be multifactorial and complex...
May 2017: Journal of Medical Microbiology
https://www.readbyqxmd.com/read/28496433/interplay-between-mutations-and-efflux-in-drug-resistant-clinical-isolates-of-mycobacterium-tuberculosis
#15
Diana Machado, Tatiane S Coelho, João Perdigão, Catarina Pereira, Isabel Couto, Isabel Portugal, Raquel De Abreu Maschmann, Daniela F Ramos, Andrea von Groll, Maria L R Rossetti, Pedro A Silva, Miguel Viveiros
Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28494730/small-molecule-efflux-pump-inhibitors-in-mycobacterium-tuberculosis-a-rational-drug-design-perspective
#16
Erika Kapp, Sarel F Malan, Samantha L Sampson
Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M...
May 9, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28493713/cetuximab-prevents-methotrexate-induced-cytotoxicity-in-vitro-through-epidermal-growth-factor-dependent-regulation-of-renal-drug-transporters
#17
Pedro Caetano-Pinto, Amer Jamalpoor, Janneke Ham, Anastasia Goumenou, Monique Mommersteeg, Dirk Pijnenburg, Rob Ruijtenbeek, Natalia Sanchez-Romero, Bertrand van Zelst, Sandra G Heil, Jitske Jansen, Martijn J Wilmer, Carla M L van Herpen, Rosalinde Masereeuw
The combination of methotrexate with epidermal growth factor receptor (EGFR) recombinant antibody, cetuximab, is currently being investigated in treatment of head and neck carcinoma. As methotrexate is cleared by renal excretion, we studied the effect of cetuximab on renal methotrexate handling. We used human conditionally immortalized proximal tubule epithelial cells overexpressing either organic anion transporter 1 or 3 (ciPTEC-OAT1/ciPTEC-OAT3) to examine OAT1 and OAT3, and the efflux pumps breast cancer resistance protein (BCRP), multidrug resistance protein 4 (MRP4), and P-glycoprotein (P-gp) in methotrexate handling upon EGF or cetuximab treatment...
June 5, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28490701/-adeabc-efflux-pump-and-resistance-of-acinetobacter-baumannii-against-carbapenem
#18
Qingya Dou, Mingxiang Zou, Jun Li, Haichen Wang, Yongmei Hu, Wen'en Liu
To investigate relationship between AdeABC efflux pump and resistance of Acinetobacter baumannii against carbapenem.
 Methods: Carbapenem-resistant strains were acquired from multistep selection resistance test by meropenem in vitro. The quantitation test for sensitivities of strains before and after induction was determined by the E-test, and carbonylcyanide-m-chlorophenylhydrazone (CCCP) inhibition test was used to screen efflux pump. PCR, sequencing analysis, or real-time PCR was used to analyze the changes of regulatory genes adeR and adeS of the AdeABC efflux pump system, or expressions of adeA, adeB, adeR, and adeS in the strains before and after induction, respectively...
April 28, 2017: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/28462872/interaction-of-ethidium-and-tetraphenylphosphonium-cations-with-salmonella-enterica-cells
#19
Valeryia Mikalayeva, Sandra Sakalauskaitė, Rimantas Daugelavičius
BACKGROUND AND OBJECTIVE: One of the main causes of bacterial resistance to antimicrobials is multidrug resistance induced by the increased efficiency of the efflux pumps. In this study we analyzed how the conditions of assay affect the efflux of indicator substrates ethidium (Et(+)) and tetraphenylphosphonium (TPP(+)) in Salmonella enterica ser. Typhimurium cells. Impact of the outer membrane permeability barrier, composition and temperature of the medium on accumulation of the indicator compounds also was analyzed...
April 17, 2017: Medicina
https://www.readbyqxmd.com/read/28461316/competitive-fitness-of-fluconazole-resistant-clinical-candida-albicans-strains
#20
Christina Popp, Irene Hampe, Tobias Hertlein, Knut Ohlsen, P David Rogers, Joachim Morschhäuser
The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of multidrug efflux pumps and ergosterol biosynthesis genes, respectively. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug...
May 1, 2017: Antimicrobial Agents and Chemotherapy
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