3-(Benzo[d][1,3]dioxol-5-ylamino)-N-(4-fluorophenyl)thiophene-2-carboxamide overcomes cancer chemoresistance via inhibition of angiogenesis and P-glycoprotein efflux pump activity

2015 ◽  
Vol 13 (14) ◽  
pp. 4296-4309 ◽  
Author(s):  
Ramesh Mudududdla ◽  
Santosh K. Guru ◽  
Abubakar Wani ◽  
Sadhana Sharma ◽  
Prashant Joshi ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Efflux Pumps ◽  
P Glycoprotein ◽  
Pump Activity ◽  
Inhibition Of Angiogenesis ◽  
Dual Inhibition ◽  
Cancer Chemoresistance

Thiophene-2-carboxamides displayed dual inhibition of angiogenesis and P-gp efflux pumps.

scholarly journals MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps

2015 ◽  
Vol 59 (7) ◽  
pp. 3853-3863 ◽  
Author(s):  
Mansi Garg ◽  
Neena Goyal
Keyword(s):  
Leishmania Donovani ◽  
Drug Sensitivity ◽  
Efflux Pump ◽  
Indian Subcontinent ◽  
Normal Growth ◽  
Efflux Pumps ◽  
Content Type ◽  
P Glycoprotein ◽  
Pump Activity ◽  
Antimony Resistance

ABSTRACTEmergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) in the Indian subcontinent. Mitogen-activated protein kinases (MAPKs) are well-known mediators of signal transduction of eukaryotes, regulating important processes, like proliferation, differentiation, stress response, and apoptosis. InLeishmania, MAPK1 has been shown to be consistently downregulated in antimony-resistant field isolates, suggesting that it has a role in antimony resistance. The present work investigates the molecular mechanism of MAPK1 in antimony resistance inLeishmania donovani. TheL. donovaniMAPK1 (LdMAPK1) single-allele replacement mutants exhibited increased resistance to Sb(III) (5.57-fold) compared to wild-type promastigotes, while overexpressing parasites became much more susceptible to antimony. The LdMAPK1-mediated drug sensitivity was directly related to antimony-induced apoptotic death of the parasite, as was evidenced by a 4- to 5-fold decrease in cell death parameters in deletion mutants and a 2- to 3-fold increase in MAPK1-overexpressing cells. LdMAPK1-underexpressing parasites also exhibited increased P-glycoprotein (P-gp)-mediated efflux pump activity, while a significant decrease in pump activity was observed in overexpressing cells. This change in efflux pump activity was directly related to expression levels of P-gp in all cell lines. However, episomal complementation of the gene restored normal growth, drug sensitivity, P-gp expression, and efflux pump activity. The data indicate that LdMAPK1 negatively regulates the expression of P-glycoprotein-type efflux pumps in the parasite. The decrease in efflux pump activity with an increase in LdMAPK1 expression may result in increased antimony accumulation in the parasite, making it more vulnerable to the drug.

scholarly journals A Combination Fluorescence Assay Demonstrates Increased Efflux Pump Activity as a Resistance Mechanism in Azole-Resistant Vaginal Candida albicans Isolates

2016 ◽  
Vol 60 (10) ◽  
pp. 5858-5866 ◽  
Author(s):  
Somanon Bhattacharya ◽  
Jack D. Sobel ◽  
Theodore C. White
Keyword(s):  
Candida Albicans ◽  
Efflux Pump ◽  
Pathogenic Fungus ◽  
Resistance Mechanism ◽  
Efflux Pumps ◽  
Resistant Isolate ◽  
Vaginal Infections ◽  
Content Type ◽  
Qrt Pcr ◽  
Pump Activity

ABSTRACTCandida albicansis a pathogenic fungus causing vulvovaginal candidiasis (VVC). Azole drugs, such as fluconazole, are the most common treatment for these infections. Recently, azole-resistant vaginalC. albicansisolates have been detected in patients with recurring and refractory vaginal infections. However, the mechanisms of resistance in vaginalC. albicansisolates have not been studied in detail. In oral and systemic resistant isolates, overexpression of the ABC transporters Cdr1p and Cdr2p and the major facilitator transporter Mdr1p is associated with resistance. Sixteen fluconazole-susceptible and 22 fluconazole-resistant vaginalC. albicansisolates were obtained, including six matched sets containing a susceptible and a resistant isolate, from individual patients. Using quantitative real-time reverse transcriptase PCR (qRT-PCR), 16 of 22 resistant isolates showed overexpression of at least one efflux pump gene, while only 1 of 16 susceptible isolates showed such overexpression. To evaluate the pump activity associated with overexpression, an assay that combined data from two separate fluorescent assays using rhodamine 6G and alanine β-naphthylamide was developed. The qRT-PCR results and activity assay results were in good agreement. This combination of two fluorescent assays can be used to study efflux pumps as resistance mechanisms in clinical isolates. These results demonstrate that efflux pumps are a significant resistance mechanism in vaginalC. albicansisolates.

Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus Nor A efflux pump

2015 ◽  
Vol 13 (19) ◽  
pp. 5424-5431 ◽  
Author(s):  
Jaideep B. Bharate ◽  
Samsher Singh ◽  
Abubakar Wani ◽  
Sadhana Sharma ◽  
Prashant Joshi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Efflux Pump ◽  
Dual Inhibitor ◽  
P Glycoprotein ◽  
Dual Inhibition ◽  
And Staphylococcus Aureus

Pyrroles showed dual inhibition of human P-gp and S. aureus Nor A efflux pump.

Efflux pump inhibition controls growth and enhances antifungal susceptibility of Fusarium solani species complex

2020 ◽  
Vol 15 (1) ◽  
pp. 9-20
Author(s):  
Rossana de A Cordeiro ◽  
Fernando VM Portela ◽  
Lívia MG Pereira ◽  
Ana RC de Andrade ◽  
José K de Sousa ◽  
...  
Keyword(s):  
Fusarium Solani ◽  
Species Complex ◽  
Efflux Pump ◽  
Antifungal Susceptibility ◽  
Indirect Evidence ◽  
Efflux Pumps ◽  
Fusarium Solani Species Complex ◽  
Efflux Pump Inhibition ◽  
Pump Activity ◽  
Increased Sensitivity

Aim: To evaluate the inhibition of efflux pumps by using promethazine (PMZ) as a strategy to control Fusarium solani species complex (FSSC). Materials & methods: The susceptibility of FSSC strains to PMZ and the interaction between PMZ and antifungals were evaluated. The efflux pump activity was confirmed by flow cytometry with rhodamine 6G. Finally, PMZ was tested against FSSC biofilms. Results: PMZ inhibited FSSC planktonic growth and showed synergism with antifungals. PMZ reduced R6G efflux and inhibited cell adhesion, impaired the development of biofilms and disrupted mature biofilms. PMZ-challenged biofilms showed increased sensitivity to amphotericin B. Conclusion: The study provides indirect evidence of the occurrence of efflux pumps in FSSC and opens a perspective for this target in the control of fusariosis.

scholarly journals Molecular and phenotypic characterization of efflux pump and biofilm in multi-drug resistant non-typhoidal Salmonella Serovars isolated from food animals and handlers in Lagos Nigeria

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Elizabeth Tolulope Olubisose ◽  
Abraham Ajayi ◽  
Adeyemi Isaac Adeleye ◽  
Stella Ifeanyi Smith
Keyword(s):  
Antibiotic Resistance ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Phenotypic Characterization ◽  
Pump Activity ◽  
Food Animals

Abstract Background Multidrug resistance efflux pumps and biofilm formation are mechanisms by which bacteria can evade the actions of many antimicrobials. Antibiotic resistant non-typhoidal Salmonella serovars have become wide spread causing infections that result in high morbidity and mortality globally. The aim of this study was to evaluate the efflux pump activity and biofilm forming capability of multidrug resistant non-typhoidal Salmonella (NTS) serovars isolated from food handlers and animals (cattle, chicken and sheep) in Lagos. Methods Forty eight NTS serovars were subjected to antibiotic susceptibility testing by the disc diffusion method and phenotypic characterization of biofilm formation was done by tissue culture plate method. Phenotypic evaluation of efflux pump activity was done by the ethidium bromide cartwheel method and genes encoding biofilm formation and efflux pump activity were determined by PCR. Results All 48 Salmonella isolates displayed resistance to one or more classes of test antibiotics with 100% resistance to amoxicillin-clavulanic acid. Phenotypically, 28 (58.3%) of the isolates exhibited efflux pump activity. However, genotypically, 7 (14.6%) of the isolates harboured acrA, acrB and tolC, 8 (16.7%) harboured acrA, acrD and tolC while 33 (68.8%) possessed acrA, acrB, acrD and tolC. All (100%) the isolates phenotypically had the ability to form biofilm with 23 (47.9%), 24 (50.0%), 1 (2.1%) categorized as strong (SBF), moderate (MBF) and weak (WBF) biofilm formers respectively but csgA gene was detected in only 23 (47.9%) of them. Antibiotic resistance frequency was significant (p < 0.05) in SBF and MBF and efflux pump activity was detected in 6, 21, and 1 SBF, MBF and WBF respectively. Conclusion These data suggest that Salmonella serovars isolated from different food animals and humans possess active efflux pumps and biofilm forming potential which has an interplay in antibiotic resistance. There is need for prudent use of antibiotics in veterinary medicine and scrupulous hygiene practice to prevent the transmission of multidrug resistant Salmonella species within the food chain.

scholarly journals Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity

2011 ◽  
Vol 55 (5) ◽  
pp. 2092-2097 ◽  
Author(s):  
Ranjith Rajendran ◽  
Eilidh Mowat ◽  
Elaine McCulloch ◽  
David F. Lappin ◽  
Brian Jones ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Dependent Manner ◽  
Content Type ◽  
Quantitative Expression ◽  
Pump Activity ◽  
Competitive Substrate

ABSTRACTThis study investigated the phase-dependent expression and activity of efflux pumps inAspergillus fumigatustreated with voriconazole. Fourteen strains were shown to become increasingly resistant in the 12-h (16- to 128-fold) and 24-h (>512-fold) phases compared to 8-h germlings. An Ala-Nap uptake assay demonstrated a significant increase in efflux pump activity in the 12-h and 24-h phases (P< 0.0001). The efflux pump activity of the 8-h germling cells was also significantly induced by voriconazole (P< 0.001) after 24 h of treatment. Inhibition of efflux pump activity with the competitive substrate MC-207,110 reduced the voriconazole MIC values for theA. fumigatusgermling cells by 2- to 8-fold. Quantitative expression analysis ofAfuMDR4mRNA transcripts showed a phase-dependent increase as the mycelial complexity increased, which was coincidental with a strain-dependent increase in azole resistance. Voriconazole also significantly induced this in a time-dependent manner (P< 0.001). Finally, anin vivomouse biofilm model was used to evaluate efflux pump expression, and it was shown thatAfuMDR4was constitutively expressed and significantly induced by treatment with voriconazole after 24 h (P< 0.01). Our results demonstrate that efflux pumps are expressed in complexA. fumigatusbiofilm populations and that this contributes to azole resistance. Moreover, voriconazole treatment induces efflux pump expression. Collectively, these data may provide evidence for azole treatment failures in clinical cases of aspergillosis.

scholarly journals High efflux pump activity and gene expression at baseline linked to poor tuberculosis treatment outcomes

2017 ◽  
Vol 6 (1) ◽  
pp. 8-17
Author(s):  
S. Mazando ◽  
C. Zimudzi ◽  
M. Zimba ◽  
S. Sande ◽  
M. Gundidza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Ethidium Bromide ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Drug Tolerance ◽  
Tuberculosis Treatment ◽  
Expression Levels ◽  
Pump Activity

Phenotypic TB drug resistance, also known as drug tolerance, has been previously attributed to slowed bacterial growth in vivo. The increased activity and expression of efflux systems can lower the intracellular concentration of many antibiotics thus reducing their efficacy. We hypothesized that efflux pump activation and expression could be a risk factor for TB drug tolerance in patients initiated on treatment. Analyses of gene expression levels of six select efflux pumps associated with drug tolerance in Mycobacterium tuberculosis and its correlation with the cell’s ability to efflux ethidium bromide (a common efflux substrate) were assayed. Efflux pump gene expression differed significantly between the strains from treatment failures and treatment successes. Efflux of ethidium bromide by M. tuberculosis isolates revealed that isolates from treatment failures rapidly efflux ethidium bromide more than isolates from treatment successes or the H37Rv control strains. The efflux pumps efpA, jefA (Rv2459c), Rv1258c, p55 and mmpL7 may have a role in TB drug tolerance. Quantifying the expression levels of M. tuberculosis efflux pump genes may be a new method to diagnose clinically persistent tuberculosis. High efflux pump activity and expression at baseline can be associated with tuberculosis treatment failure even when the Mycobacterium tuberculosis does not have established resistance mutations.Journal of Medical and Biomedical Sciences (2017) 6(1), 8-17Keywords: drug resistance, Efflux, Mycobacterium tuberculosis, expression, treatment outcome

scholarly journals How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Jessica M. A. Blair ◽  
Laura J. V. Piddock
Keyword(s):  
Mass Spectrometry ◽  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Scientific Literature ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Biofuel Production ◽  
Intracellular Accumulation ◽  
Pump Activity ◽  
Biotechnological Processes

ABSTRACT Bacterial multidrug resistance (MDR) efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i) those that directly measure efflux and (ii) those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity.

scholarly journals Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 18
Author(s):  
Henry Döring ◽  
David Kreutzer ◽  
Christoph Ritter ◽  
Andreas Hilgeroth
Keyword(s):  
Cell Line ◽  
Efflux Pump ◽  
Metastatic Cancer ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Clinical Settings ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Overexpressing Cell ◽  
Molecular Framework

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

P-glycoprotein efflux pump expression and activity in Calu-3 cells

2001 ◽  
Vol 90 (5) ◽  
pp. 645
Author(s):  
Karen O. Hamilton ◽  
Gunilla Backstrom ◽  
Mehran A. Yazdanian ◽  
Kenneth L. Audus
Keyword(s):  
Efflux Pump ◽  
P Glycoprotein ◽  
Expression And Activity
Sign in / Sign up

Export Citation Format

Share Document