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efflux pump inhibition

Ilyas Alav, J Mark Sutton, Khondaker Miraz Rahman
Efflux pumps are widely implicated in antibiotic resistance because they can extrude the majority of clinically relevant antibiotics from within cells to the extracellular environment. However, there is increasing evidence from many studies to suggest that the pumps also play a role in biofilm formation. These studies have involved investigating the effects of efflux pump gene mutagenesis and efflux pump inhibitors on biofilm formation, and measuring the levels of efflux pump gene expression in biofilms. In particular, several key pathogenic species associated with increasing multidrug resistance, such as Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, have been investigated, whilst other studies have focused on Salmonella enterica serovar Typhimurium as a model organism and problematic pathogen...
February 28, 2018: Journal of Antimicrobial Chemotherapy
Yanyan Jia, Samir Kumar Khanal, Haoyue Shu, Huiqun Zhang, Guang-Hao Chen, Hui Lu
Ciprofloxacin (CIP), a fluoroquinolone antibiotic, removal was examined for the first time, in an anaerobic sulfate-reducing bacteria (SRB) sludge system. About 28.0% of CIP was biodegraded by SRB sludge when the influent CIP concentration was 5000 μg/L. Some SRB genera with high tolerance to CIP (i.e. Desulfobacter), were enriched at CIP concentration of 5000 μg/L. The changes in antibiotic resistance genes (ARGs) of SRB sludge coupled with CIP biodegradation intermediates were used to understand the mechanism of CIP biodegradation for the first time...
February 26, 2018: Water Research
Jennifer Ryan, Ryan E Morgan, Yuan Chen, Laurie Volak, Robert T Dunn, Kenneth W Dunn
The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury (DILI) that often goes undetected during non-clinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow-up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models...
February 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Annamária Kincses, Borisz Varga, Ákos Csonka, Shirley Sancha, Silva Mulhovo, Ana Margarida Madureira, Maria-José U Ferreira, Gabriella Spengler
Cleistochlamys kirkii (Benth) Oliv. (Annonaceae) is a medicinal plant traditionally used in Mozambique to treat infectious diseases. The aim of this study was to find resistance modifiers in C. kirkii for Gram-positive and Gram-negative model bacterial strains. One of the most important resistance mechanisms in bacteria is the efflux pump-related multidrug resistance. Therefore, polycarpol (1), three C-benzylated flavanones (2-4), and acetylmelodorinol (5) were evaluated for their multidrug resistance-reverting activity on methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Escherichia coli AG100 and AG100 A strains overexpressing and lacking the AcrAB-TolC efflux pump system...
February 21, 2018: Phytotherapy Research: PTR
Chao Chen, Susana Gardete, Robert Sander Jansen, Annanya Shetty, Thomas Dick, Kyu Y Rhee, Véronique Dartois
Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb's efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil's synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Imran Shair Mohammad, Wei He, Lifang Yin
Indeed, multi-drug resistance (MDR) is a significant obstacle to effective chemotherapy. The overexpression of ATP-binding cassette (ABC) membrane transporters is a principal cause of enhanced cytotoxic drug efflux and treatment failure in various types of cancers. At cellular level, the pumps of ABC family regulate the transportation of numerous substances including drugs in and out of the cells. In past, the overexpression of ABC pumps suggested a well-known mechanism of drug resistance in cancers as well as infectious diseases...
February 13, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Lisa Chedik, Arnaud Bruyere, Olivier Fardel
1. Organophosphorus pesticides (OPs) are known to interact with human ATP-binding cassette drug efflux pumps. The present study was designed to determine whether they can also target activities of human solute carrier (SLC) drug transporters. 2. The interactions of thirteen OPs with SLC transporters involved in drug disposition, such as organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), were mainly investigated using transporter-overexpressing cell clones and fluorescent or radiolabeled reference substrates...
February 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Hai Wang, Zan Gao, Xuanyou Liu, Pranay Agarwal, Shuting Zhao, Daniel W Conroy, Guang Ji, Jianhua Yu, Christopher P Jaroniec, Zhenguo Liu, Xiongbin Lu, Xiaodong Li, Xiaoming He
Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD+ to reduce the amount of ATP available for the efflux pumps...
February 8, 2018: Nature Communications
Silvia Dei, Marcella Coronnello, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Chatchanok Udomtanakunchai, Milena Salerno, Elisabetta Teodori
A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin uptake assay on the doxorubicin-resistant erythroleukemia K562 cells (K562/DOX). In particular, compounds bearing methoxy aromatic moieties showed fairly high reversal activities...
February 5, 2018: European Journal of Medicinal Chemistry
Milan Hano, Lenka Tomášová, Mário Šereš, Lucia Pavlíková, Albert Breier, Zdena Sulová
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1 member of the ABC transporter gene family)-is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR)...
February 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Sebastian C Köhler, Sahel Vahdati, Matthias S Scholz, Michael Wiese
An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors...
January 11, 2018: European Journal of Medicinal Chemistry
Fen Su, Jiliang Wang
Pseudomonas (P.) aeruginosa is an ubiquitous and metabolically versatile opportunistic pathogen and may cause various life-threatening diseases. Due to increasing emergence of resistance to carbapenems, novel drugs with improved antibacterial activities compared with those of traditional antibiotics are required. In the present study, berberine (BEB), a natural isoquinoline alkaloid, was used in combination with imipenem (IMP), a commonly-used carbapenem, to investigate their antibacterial activities against a clinical P...
January 2018: Experimental and Therapeutic Medicine
Chengcheng Hu, Mi Zhou, Wenzhao Wang, Xianyun Sun, Oded Yarden, Shaojie Li
Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis. To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol. Using an inducible promoter to regulate Neurospora crassa erg11, which encodes the major azole target, sterol 14α-demethylase, we were able to demonstrate that the CDR4 azole efflux pump can be transcriptionally activated by ergosterol biosynthesis inhibition even in the absence of azoles...
2018: Frontiers in Microbiology
Kara C Evans, Saida Benomar, Lennel A Camuy-Vélez, Ellen B Nasseri, Xiaofei Wang, Benjamin Neuenswander, Josephine R Chandler
Many Proteobacteria use quorum sensing to regulate production of public goods, such as antimicrobials and proteases, that are shared among members of a community. Public goods are vulnerable to exploitation by cheaters, such as quorum sensing-defective mutants. Quorum sensing- regulated private goods, goods that benefit only producing cells, can prevent the emergence of cheaters under certain growth conditions. Previously, we developed a laboratory co-culture model to investigate the importance of quorum-regulated antimicrobials during interspecies competition...
January 26, 2018: ISME Journal
Malkeet Kumar, Kawaljit Singh, Andile H Ngwane, Fahreta Hamzabegovic, Getahun Abate, Bienyameen Baker, Ian Wiid, Daniel F Hoft, Peter Ruminski, Kelly Chibale
Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M...
December 29, 2017: Bioorganic & Medicinal Chemistry
Sandip B Bharate, Vikas Kumar, Shreyans K Jain, Mubashir Javeed Mintoo, Santosh Kumar Guru, Vijay K Nuthakki, Mohit Sharma, Sonali S Bharate, Sumit G Gandhi, Dilip Manikrao Mondhe, Shashi Bhushan, Ram A Vishwakarma
Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via IV route. With the objective to address oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1...
January 25, 2018: Journal of Medicinal Chemistry
Shayna Sandhaus, Prem P Chapagain, Yuk-Ching Tse-Dinh
Topoisomerases are important targets for antibacterial and anticancer therapies. Bacterial topoisomerase I remains to be exploited for antibiotics that can be used in the clinic. Inhibitors of bacterial topoisomerase I may provide leads for novel antibacterial drugs against pathogens resistant to current antibiotics. TB is the leading infectious cause of death worldwide, and new TB drugs against an alternative target are urgently needed to overcome multi-drug resistance. Mycobacterium tuberculosis topoisomerase I (MtbTopI) has been validated genetically and chemically as a TB drug target...
January 23, 2018: Scientific Reports
Greg Hodge, Sandra Hodge, Phan Tien Nguyen, Aeneas Yeo, Parama Sarkar, Arash Badiei, C L Holmes-Liew, Paul N Reynolds, Mark Holmes
Immunosuppressive therapy fails to suppress the production of pro-inflammatory cytokines, particularly by CD8+T cells, in stable lung transplant recipients and those undergoing chronic rejection, suggesting that some patients may become relatively resistant to immunosuppressants such as glucocorticoids (GC). We have shown loss of GC receptor (GCR) from the CD8+ cells, and we hypothesized that the drug membrane efflux pump, p-glycoprotein-1 (Pgp), may also be involved in lymphocyte steroid resistance following lung transplant...
January 20, 2018: Clinical and Experimental Immunology
Cynthia A Danquah, Eleftheria Kakagianni, Proma Khondkar, Arundhati Maitra, Mukhlesur Rahman, Dimitrios Evangelopoulos, Timothy D McHugh, Paul Stapleton, John Malkinson, Sanjib Bhakta, Simon Gibbons
Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl methanethiosulfonate, exhibited antimicrobial activity, with one compound inhibiting the growth of Mycobacterium tuberculosis at 17 µM (4 mg L-1) and other compounds inhibiting Escherichia coli and multi-drug-resistant (MDR) Staphylococcus aureus at concentrations ranging between 32-138 µM (8-32 mg L-1)...
January 18, 2018: Scientific Reports
Liuqing Yang, Manman Li, Yusheng Sun, Liefeng Zhang
In this study, a cell-penetrating peptide conjugate, R8-carboxymethyl-β-cyclodextrin (R8-CM-β-CD), was synthesized, and then we prepared the supramolecular complex (insulin/R8-CM-β-CD). The physicochemical properties of the complex were characterized. The supramolecular complex could facilitate the uptake of insulin, meanwhile, induce a significantly higher internalization of insulin. Interestingly, the transportation efficiency of insulin/R8-CM-β-CD across the Caco-2 cell monolayer was about 3 times greater than that of insulin/CM-β-CD...
January 14, 2018: International Journal of Biological Macromolecules
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