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efflux pump inhibition

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https://www.readbyqxmd.com/read/28720734/lack-of-acrb-efflux-function-confers-loss-of-virulence-on-salmonella-enterica-serovar-typhimurium
#1
Xuan Wang-Kan, Jessica M A Blair, Barbara Chirullo, Jonathan Betts, Roberto M La Ragione, Alasdair Ivens, Vito Ricci, Timothy J Opperman, Laura J V Piddock
AcrAB-TolC is the paradigm resistance-nodulation-division (RND) multidrug resistance efflux system in Gram-negative bacteria, with AcrB being the pump protein in this complex. We constructed a nonfunctional AcrB mutant by replacing D408, a highly conserved residue essential for proton translocation. Western blotting confirmed that the AcrB D408A mutant had the same native level of expression of AcrB as the parental strain. The mutant had no growth deficiencies in rich or minimal medium. However, compared with wild-type SL1344, the mutant had increased accumulation of Hoechst 33342 dye and decreased efflux of ethidium bromide and was multidrug hypersusceptible...
July 18, 2017: MBio
https://www.readbyqxmd.com/read/28715978/the-role-of-efflux-pumps-in-tuberculosis-treatment-and-their-promise-as-a-target-in-drug-development-unraveling-the-black-box
#2
Lindsey H M Te Brake, Gerjo J de Knegt, Jurriaan E de Steenwinkel, Teunis J P van Dam, David M Burger, Frans G M Russel, Reinout van Crevel, Jan B Koenderink, Rob E Aarnoutse
Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents...
July 17, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28710521/efflux-drug-transporters-at-the-forefront-of-antimicrobial-resistance
#3
REVIEW
Tahmina Rahman, Benjamin Yarnall, Declan A Doyle
Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man's discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these responses involves the use of antibiotic efflux transporters...
July 14, 2017: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/28709374/nanoparticles-as-efflux-pump-and-biofilm-inhibitor-to-rejuvenate-bactericidal-effect-of-conventional-antibiotics
#4
REVIEW
Divya Gupta, Ajeet Singh, Asad U Khan
The universal problem of bacterial resistance to antibiotic reflects a serious threat for physicians to control infections. Evolution in bacteria results in the development of various complex resistance mechanisms to neutralize the bactericidal effect of antibiotics, like drug amelioration, target modification, membrane permeability reduction, and drug extrusion through efflux pumps. Efflux pumps acquire a wide range of substrate specificity and also the tremendous efficacy for drug molecule extrusion outside bacterial cells...
December 2017: Nanoscale Research Letters
https://www.readbyqxmd.com/read/28700974/mechanism-of-berberine-mediated-fluconazole-susceptibility-enhancement-in-clinical-fluconazole-resistant-candida-tropicalis-isolates
#5
GaoXiang Shi, Jing Shao, TianMing Wang, DaQiang Wu, ChangZhong Wang
BACKGROUND: Candida tropicalis was one of the most common non-albicans Candida (NACA) species creating relatively high morbidity and mortality. We previously demonstrated that the antifungal effect of BBR in combination with FLC might be attributed to reactive oxygen species production, ergosterol content and efflux pump levels in a clinical C. tropicalis isolate. METHODS: we employed thirteen clinical C. tropicalis isolates as well as four standard reference strains to evaluate the antifungal activity of BBR in combination with FLC under planktonic and biofilm states by analyzing the mRNA expressions of ERG11, CDR1 and MDR1 by qRT-PCR...
July 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28700656/unexpected-effects-of-azole-transporter-inhibitors-on-antifungal-susceptibility-in-candida-glabrata-and-other-pathogenic-candida-species
#6
Yohsuke Nagayoshi, Taiga Miyazaki, Shintaro Shimamura, Hironobu Nakayama, Asuka Minematsu, Shunsuke Yamauchi, Takahiro Takazono, Shigeki Nakamura, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae, Koichi Izumikawa
The pathogenic fungus Candida glabrata is often resistant to azole antifungal agents. Drug efflux through azole transporters, such as Cdr1 and Cdr2, is a key mechanism of azole resistance and these genes are under the control of the transcription factor Pdr1. Recently, the monoamine oxidase A (MAO-A) inhibitor clorgyline was shown to inhibit the azole efflux pumps, leading to increased azole susceptibility in C. glabrata. In the present study, we have evaluated the effects of clorgyline on susceptibility of C...
2017: PloS One
https://www.readbyqxmd.com/read/28698674/insight-into-synergetic-mechanisms-of-tetracycline-and-the-selective-serotonin-reuptake-inhibitor-sertraline-in-a-tetracycline-resistant-strain-of-escherichia-coli
#7
Lili Li, Sofie Kromann, John Elmerdahl Olsen, Søren Wedel Svenningsen, Rikke Heidemann Olsen
Sertraline, an antidepressive drug, has been reported to inhibit general bacterial efflux pumps. In the present study, we report for the first time a synergistic effect of sertraline and tetracycline in a TetA-encoded tetracycline-resistant strain of Escherichia coli. Synergy between sertraline and tetracycline in an E. coli strain with TetA-mediated tetracycline resistance (E. coli APEC_O2) was assessed by the MIC and checkerboard assays. The global transcriptome of E. coli APEC_O2 exposed to ½ MIC concentrations of sertraline and/or tetracycline was analyzed to elucidate the interaction mechanism between sertraline and tetracycline...
July 12, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28675836/natural-alkaloids-as-p-gp-inhibitors-for-multidrug-resistance-reversal-in-cancer
#8
REVIEW
Prashant Joshi, Ram A Vishwakarma, Sandip B Bharate
The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents. The clinical failure of first and second generation P-gp inhibitors (such as verapamil and cyclosporine analogs) has led to the discovery of third generation potent P-gp inhibitors (tariquidar, zosuquidar, laniquidar)...
June 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28673609/strong-synergism-of-dexamethasone-in-combination-with-fluconazole-against-resistant-candida-albicans-mediated-by-inhibiting-drug-efflux-and-reducing-virulence
#9
Wenwen Sun, Decai Wang, Cuixiang Yu, Xin Huang, Xiuyun Li, Shujuan Sun
Candida albicans are the most common isolated strains in the clinic and their resistance to fluconazole has beenemergingrapidly.Combinatorial therapy would be is a potentially effective approach against drugresistance. In this study, the combinatorial antifungal effects of dexamethasone and fluconazoleagainst resistant Candida albicans in vitrowere assayed usingminimum inhibitory concentrations, sessile minimum inhibitory concentrations, and time-kill curves. In vivo efficacy of this drug combination was evaluated usingthe Galleria mellonellamodel...
June 30, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28669880/role-of-vitamin-d-in-amyloid-clearance-via-lrp-1-upregulation-in-alzheimer-s-disease-a-potential-therapeutic-target
#10
REVIEW
Parmi Patel, Jigna Shah
Amyloid beta (Aβ) deposition is considered to be one of the primary reason to trigger Alzheimer's disease (AD). Literature clearly suggests decline in Aβ clearance to be accountable for progression of late onset AD as compared to augmented Aβ production. There may be several pathways for Aβ clearance out of which one of the major pathway is the vascular-mediated removal of Aβ from the brain across the blood-brain barrier (BBB) via efflux pumps or receptors. Among Aβ scavenger receptors, low density lipoprotein receptor related protein (LRP-1) has been most extensively studied...
June 30, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28665551/mechanistic-differences-in-the-uptake-of-salicylic-acid-glucose-conjugates-by-vacuolar-membrane-enriched-vesicles-isolated-from-arabidopsis-thaliana
#11
Elizabeth Vaca, Claire Behrens, Tiju Theccanat, Jun-Yong Choe, John V Dean
Salicylic acid (SA) is a plant hormone involved in a number of physiological responses including both local and systemic resistance of plants to pathogens. In Arabidopsis, SA is glucosylated to form either SA 2-O-β-D-glucose (SAG) or SA glucose ester (SGE). In the present study, we show that SAG accumulates in the vacuole of Arabidopsis, while the majority of SGE was located outside the vacuole. The uptake of SAG by vacuolar membrane-enriched vesicles isolated from Arabidopsis was stimulated by the addition of MgATP and was inhibited by both vanadate (ABC transporter inhibitor) and bafilomycin A1 (vacuolar H(+) -ATPase inhibitor), suggesting that SAG uptake involves both an ABC transporter and H(+) -antiporter...
June 30, 2017: Physiologia Plantarum
https://www.readbyqxmd.com/read/28650638/identification-and-structure-activity-relationships-of-novel-compounds-that-potentiate-the-activities-of-antibiotics-in-escherichia-coli
#12
Keith M Haynes, Narges Abdali, Varsha Jhawar, Helen I Zgurskaya, Jerry M Parks, Adam T Green, Jerome Yves Baudry, Valentin V Rybenkov, Jeremy C Smith, John K Walker
In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB-TolC efflux pump in E...
June 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28623111/reversal-of-abcb1-mediated-efflux-by-imatinib-and-nilotinib-in-cells-expressing-various-transporter-levels
#13
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
#14
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...
July 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
#15
Durairaj Thiyagarajan, Gopal Das, Aiyagari Ramesh
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 the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC was found to render 8- and 6-fold decreases in the minimum biofilm eradication concentration (MBEC90 ) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in the case of gentamicin, C1-PNC promotes enhanced cellular uptake of the antibiotic, whereas 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
#16
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
#17
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
#18
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
#19
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
#20
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
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