Indole derivatives as efflux pump inhibitors for TolC protein in a clinical drug-resistant Escherichia coli isolated from a pig farm

2008 ◽  
Vol 31 (5) ◽  
pp. 497-498 ◽  
Author(s):  
Jingyuan Tang ◽  
Hongning Wang
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Drug Resistant ◽  
Indole Derivatives ◽  
Pig Farm ◽  
Tolc Protein ◽  
Efflux Pump Inhibitors ◽  
Clinical Drug

scholarly journals Brown and Red Seaweeds Serve as Potential Efflux Pump Inhibitors for Drug-Resistant Escherichia coli

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Wen-Jung Lu ◽  
Hsuan-Ju Lin ◽  
Pang-Hung Hsu ◽  
Margaret Lai ◽  
Jen-Yu Chiu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Synergistic Effects ◽  
Laminaria Japonica ◽  
Biologically Active ◽  
Drug Resistant ◽  
Active Metabolites ◽  
Pyrrole Derivatives ◽  
Red Seaweeds ◽  
Efflux Pump Inhibitors

Multidrug-resistant pathogens are a significant clinical problem. Efflux pump inhibitors (EPIs) can restore the activities of existing antibiotics by interfering with drug efflux pumps located in bacterial cell membranes. Seaweeds are important sources of biologically active metabolites of natural origin; however, their potential as EPIs remains uninvestigated. Here, functional extracts from the brown seaweeds Laminaria japonica and Sargassum horneri and the red seaweeds Gracilaria sp. and Porphyra dentata were evaluated as potential EPIs against drug-resistant Escherichia coli. All these extracts were found to potentiate the activities of drugs in modulation tests, although not to the same extent. Synergistic effects of the extracts and the drug clarithromycin were observed from the onset of Time-kill assays, with no evidence of bacterial regrowth. Ethidium bromide accumulation studies revealed that the efflux decreased in the presence of each extract, as indicated by the presence of EPIs. Most identified EPIs that have been discovered to date have aromatic structures, and the seaweed extracts were found to contain various terpenes, terpenoids, phenolic compounds, indoles, pyrrole derivatives, alkaloids, and halogenated aromatic compounds. Our study highlights the potential of these compounds of the seaweeds as drug EPIs.

scholarly journals 1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

2019 ◽  
Vol 20 (7) ◽  
pp. 1699 ◽  
Author(s):  
Anton Shetnev ◽  
Sergey Baykov ◽  
Stanislav Kalinin ◽  
Alexandra Belova ◽  
Vladimir Sharoyko ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Efflux Pump ◽  
Ductal Adenocarcinoma ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Drug Resistant Bacteria ◽  
Efflux Pump Inhibitors

Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.

scholarly journals Isolation and Characterization of VceC Gain-of-Function Mutants That Can Function with the AcrAB Multiple-Drug-Resistant Efflux Pump of Escherichia coli

2006 ◽  
Vol 188 (11) ◽  
pp. 3757-3762 ◽  
Author(s):  
Govindsamy Vediyappan ◽  
Tatyana Borisova ◽  
Joe A. Fralick
Keyword(s):  
Escherichia Coli ◽  
Outer Membrane ◽  
Efflux Pump ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Membrane Component ◽  
Gain Of Function ◽  
Isolation And Characterization ◽  
Multiple Drug Resistant ◽  
Major Facilitator

ABSTRACT VceC is the outer membrane component of the major facilitator (MF) VceAB-VceC multiple-drug-resistant (MDR) efflux pump of Vibrio cholerae. TolC is the outer membrane component of the resistance-nodulation-division AcrAB-TolC efflux pump of Escherichia coli. Although these proteins share little amino acid sequence identity, their crystal structures can be readily superimposed upon one another. In this study, we have asked if TolC and VceC are interchangeable for the functioning of the AcrAB and VceAB pumps. We have found that TolC can replace VceC to form a functional VceAB-TolC MDR pump, but VceC cannot replace TolC to form a functional AcrAB-VceC pump. However, we have been able to isolate gain-of-function (gof) VceC mutants which can functionally interface with AcrAB. These mutations map to four different amino acids located at the periplasmic tip of VceC. Chemical cross-linkage experiments indicate that both wild-type and gof mutant VceC can physically interact with the AcrAB complex, suggesting that these gof mutations are not affecting the recruitment of VceC to the AcrAB complex but rather its ability to functionally interface with the AcrAB pump.

scholarly journals Whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: Phylogenomic changes, virulence and resistant genes

2020 ◽  
Author(s):  
Jacob Stanley Iramiot ◽  
Henry Kajumbula ◽  
Joel Bazira ◽  
Etienne P. de Villiers ◽  
Benon B. Asiimwe
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Whole Genome ◽  
Beta Lactamase ◽  
Drug Resistant ◽  
Genome Sequences ◽  
E Coli ◽  
Resistant Genes ◽  
Pastoralist Community ◽  
Western Uganda

AbstractBackgroundThe crisis of antimicrobial resistance is already here with us, affecting both humans and animals alike and very soon, small cuts and surgeries will become life threatening. This study aimed at determine the whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: phylogenomic changes, virulence and resistant genes.MethodsThis was a laboratory based cross sectional study. Bacterial isolates analyzed in this study were 42 multidrug resistant E. coli isolated from stool samples from both humans and cattle in pastoralist communities collected between January 2018-March 2019. Most of the isolates (41/42) were resistant to three or more antibiotics (multi-drug resistant) and 21/42 isolates were ESBL producers; 13/42 from human and 8/42 from cattle. Whole Genome Sequencing (WGS) was carried out at the facilities of Kenya Medical Research Institute-Wellcome trust, Kilifi, to determine the phylogenomic changes, virulence and resistant genes.ResultsThe genomes of the human E. coli generally clustered together and away from those of cattle origin. The E. coli isolates were assigned to eight different phylogroups: A, B1, B2, Cladel, D, E, F and G, with a majority being assigned to phylogroup A; while most of the animal isolates were assigned to phylogroup B1. The carriage of multiple AMR genes was higher from the E. coli population from humans than those from cattle. Among these were Beta-lactamase; blaOXA-1: Class D beta-lactamases; blaTEM-1, blaTEM-235: Beta-lactamase; catA1: chloramphenicol acetyl transferase; cmlA1: chloramphenicol efflux transporter; dfrA1, dfrA12, dfrA14, dfrA15, dfrA17, dfrA5, dfrA7, dfrA8: macrolide phosphotransferase; oqxB11: RND efflux pump conferring resistance to fluoroquinolone; qacL, qacEdelta1: quinolone efflux pump; qnrS1: quinolone resistance gene; sul1, sul2, sul3: sulfonamide resistant; tet(A), tet(B): tetracycline efflux pump.A high variation of virulence genes was registered among the E. coli genomes from humans than those of cattle origin.ConclusionThe E. coli of human and cattle origin are largely independent with different ancestral origins. Limited sharing of strains and resistance genes presents a challenge to the hypothesis that AMR in humans is as a result of antibiotic misuse on the farm.

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.

1991 ◽  
Vol 9 (1) ◽  
pp. 17-24 ◽  
Author(s):  
T P Miller ◽  
T M Grogan ◽  
W S Dalton ◽  
C M Spier ◽  
R J Scheper ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Continuous Infusion ◽  
Efflux Pump ◽  
Competitive Inhibition ◽  
Transmembrane Protein ◽  
Immunohistochemical Method ◽  
High Dose ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Clinical Drug

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.

scholarly journals pH Modulation of Efflux Pump Activity of Multi-Drug Resistant Escherichia coli: Protection During Its Passage and Eventual Colonization of the Colon

PLoS ONE ◽  
2009 ◽  
Vol 4 (8) ◽  
pp. e6656 ◽  
Author(s):  
Ana Martins ◽  
Gabriella Spengler ◽  
Liliana Rodrigues ◽  
Miguel Viveiros ◽  
Jorge Ramos ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Drug Resistant ◽  
Pump Activity

scholarly journals Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6996
Author(s):  
Giada Cernicchi ◽  
Tommaso Felicetti ◽  
Stefano Sabatini
Keyword(s):  
Efflux Pump ◽  
Specific Resistance ◽  
Resistance Mechanisms ◽  
Future Research ◽  
Indole Derivatives ◽  
Great Opportunity ◽  
Structure Activity ◽  
New Antibiotics ◽  
Efflux Pump Inhibitors ◽  
Inhibitory Drug

Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile.

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