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efflux pump inhibition

Mitali Mishra, Satish Kumar, Rakesh K Majhi, Luna Goswami, Chandan Goswami, Harapriya Mohapatra
Antibacterial therapy is of paramount importance in treatment of several acute and chronic infectious diseases caused by pathogens. Over the years extensive use and misuse of antimicrobial agents has led to emergence of multidrug resistant (MDR) and extensive drug resistant (XDR) pathogens. This drastic escalation in resistant phenotype has limited the efficacy of available therapeutic options. Thus, the need of the hour is to look for alternative therapeutic approaches to mitigate healthcare concerns caused due to MDR bacterial infections...
2018: Frontiers in Microbiology
Cláudia P Godinho, Catarina S Prata, Sandra N Pinto, Carlos Cardoso, Narcisa M Bandarra, Fábio Fernandes, Isabel Sá-Correia
Saccharomyces cerevisiae has the ability to become less sensitive to a broad range of chemically and functionally unrelated cytotoxic compounds. Among multistress resistance mechanisms is the one mediated by plasma membrane efflux pump proteins belonging to the ABC superfamily, questionably proposed to enhance the kinetics of extrusion of all these compounds. This study provides new insights into the biological role and impact in yeast response to acetic acid stress of the multistress resistance determinant Pdr18 proposed to mediate ergosterol incorporation in plasma membrane...
May 18, 2018: Scientific Reports
Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Paulo W Limaverde, Fernando G Figueredo, Fábia F Campina, Francisco A B da Cunha, Roger H S da Costa, Pedro Silvino Pereira, Luciene F Lima, Yedda M L S de Matos, Henrique Douglas Melo Coutinho, José P Siqueira-Júnior, Valdir Q Balbino, Teresinha Gonçalves da Silva
This study was carried out to test the essential oil from C. ambrosioides leaves and its main constituent, α-Terpinene, in an antibacterial activity assay. As well, it was evaluated ability reduce resistance to norfloxacin and ethidium bromide was compared the Staphylococcus aureus 1199B whith 1199 wild type strain. The MIC of the C. ambrosioides essential oil and α-Terpinene were determined by microdilution method. The MIC of the essential oil and α-Terpinene presented a value ≥ 1024 μg/mL. However, when associated with antibacterials, the essential oil from C...
October 1, 2018: Food Chemistry
Zhaolin Chen, Cheng Huang, Taotao Ma, Ling Jiang, Liqin Tang, Tianlu Shi, Shantang Zhang, Lei Zhang, Pengli Zhu, Jun Li, Aizong Shen
BACKGROUND: Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators...
April 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Li Yang, Manjun Li, Fang Wang, Chen Zhen, Min Luo, Xiaona Fang, Hong Zhang, Jianye Zhang, Qingshan Li, Liwu Fu
BACKGROUND/AIMS: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. METHODS: The cell proliferation was detected by MTT assay...
May 5, 2018: Cellular Physiology and Biochemistry
Li-Min Wang, Ming-Yuan Zhang, Qiu-Shuang Zhu, Chun-Feng Lu, Xue Bai
BACKGROUND: Long-term chemotherapy reduces the sensitivity of colon cancer cells to chemotherapeutics like vincristine (VCR) and lead to drug resistance, which has become a major barrier for colon cancer treatment. Calcium antagonists are used as clinical tumor multidrug resistance reversal agents to regulate the P-glycoprotein (P-gp) level and block efflux pump function now, but they have significant side effects. Hyperin as active component with low toxicity in traditional Chinese medicine has calcium antagonistic effect...
March 1, 2018: Clinical Laboratory
Hye-Rim Kim, Dongsup Lee, Yong-Bin Eom
Stenotrophomonas maltophilia is a multi-drug resistant opportunistic pathogen that causes nosocomial infections in immunocompromised patients. This pathogen is difficult to treat owing to its intrinsic multidrug resistance and ability to form antimicrobial-tolerant biofilms. In the present study, we aimed to assess the potential use of celastrol as a novel anti-biofilm and/or anti-virulence agent against S. maltophilia . Results showed that celastrol at its sub-inhibitory doses decreased biofilm formation and disrupt the established biofilms produced by S...
2018: International Journal of Medical Sciences
Sophie A Baron, Jean-Marc Rolain
Objectives: Efflux in bacteria is a ubiquitous mechanism associated with resistance to antimicrobials agents. Efflux pump inhibitors (EPIs) have been developed to inhibit efflux mechanisms and could be a good alternative to reverse colistin resistance, but only CCCP has shown good activity. The aim of our study was to identify CCCP activity in a collection of 93 Gram-negative bacteria with known and unknown colistin resistance mechanisms including isolates with mcr-1 plasmid-mediated colistin resistance...
April 26, 2018: Journal of Antimicrobial Chemotherapy
Diana Machado, Jéssica Antunes, Ana Simões, João Perdigão, Isabel Couto, Matthew McCusker, Marta Martins, Isabel Portugal, Teresa Pacheco, Judite Batista, Cristina Toscano, Miguel Viveiros
PURPOSE: The mechanisms underlying colistin heteroresistance in Acinetobacter baumannii are not fully understood. Here, we investigated the role of efflux in colistin-heteroresistant populations of a multidrug-resistant (MDR) A. baumannii clinical isolate. METHODOLOGY: Three colistin-resistant A. baumannii strain variants isolated from the same clinical sample were studied for the presence of heteroresistance to colistin by drug susceptibility testing, genotyping and drug resistance target mutation analysis...
May 2, 2018: Journal of Medical Microbiology
Hikmate Abriouel, Leyre Lavilla Lerma, Beatriz Pérez Montoro, Esther Alonso, Charles W Knapp, Natacha Caballero Gómez, Antonio Gálvez, Nabil Benomar
We evaluated the efficacy of a new disinfectant product, HLE, to inhibit multiple species of planktonic and biofilm bacterial cultures. The HLE disinfectant comprised of EDTA, lactic acid and hydrogen peroxide, and our data indicated that the disinfectant had effective antimicrobial and anti-biofilm activity even at low concentrations (0.15% to 0.4% HLE, v/v). Furthermore, the HLE disinfectant destabilized biofilm structures eradicated them due to the synergistic effect of EDTA and both antimicrobials (lactic acid and hydrogen peroxide), as revealed by confocal laser scanning microscopy...
April 25, 2018: Environmental Research
Tianzhi Yang, Laine Ferrill, Leanne Gallant, Sarah McGillicuddy, Tatiana Fernandes, Nicole Schields, Shuhua Bai
Riluzole is currently one of two approved medications for the treatment of amyotrophic lateral sclerosis (ALS). However, brain disposition of riluzole, as a substrate of P-glycoprotein (P-gp), is limited by the efflux transporters at the blood-brain barrier (BBB). We propose to develop a liposomal co-delivery system that could effectively transport riluzole to brain cells by reducing efflux pumps with a P-gp inhibitor, verapamil. Riluzole and verapamil cocktail liposomes were prepared by lipid film hydration...
April 25, 2018: European Journal of Pharmaceutical Sciences
Mohammed A Baghdadi, Fahad A Al-Abbasi, Ali M El-Halawany, Ali H Aseeri, Ahmed M Al-Abd
Napthoquinones and coumarins are naturally occurring compounds with potential anticancer activity. In the current study, two O -naphthoquinons (mansonone-G and mansonone-N) and six coumarins (mansorin-A, mansorin-B, mansorin-C, mansorins-I, mansorin-II, and mansorin-III) were isolated from the heartwood of Mansonia gagei family Sterculariaceae. Isolated compounds were examined for their potential anticancer activity against breast (MCF-7), cervix (HeLa), colorectal (HCT-116) and liver (HepG2) cancer cells using Sulfarhodamine-B (SRB) assay...
April 26, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Sally A Sabra, Ahmed O Elzoghby, Salah A Sheweita, Medhat Haroun, Maged W Helmy, Maha A Eldemellawy, Ying Xia, David Goodale, Alison L Allan, Sohrab Rohani
Protein-based micelles have shown significant potential for tumor-targeted delivery of anti-cancer drugs. In this light, self-assembled nanocarriers based on GRAS (Generally recognized as safe) amphiphilic protein co-polymers were synthesized via carbodiimide coupling reaction. The new nano-platform is composed of the following key components: i) hydrophobic zein core to encapsulate the hydrophobic drugs rapamycin (RAP) and wogonin (WOG) with high encapsulation efficiency, ii) hydrophilic lactoferrin (Lf) corona to enhance the tumor targeting, and prolong systemic circulation of the nanocarriers, and iii) glutaraldehyde (GLA)-crosslinking to reduce the particle size and improve micellar stability...
April 21, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Lina M Alnajjar, Nailya R Bulatova, Rula M Darwish
OBJECTIVES: In this study we aimed to evaluate the ability of four calcium channel blockers, verapamil, diltiazem, nicardipine and nifedipine to enhance sensitivity of Candida glabrata strains to fluconazole. METHODS: The synergistic antifungal effect was examined by checkerboard method; fractional inhibitory concentration index (FIC) was determined. Time-kill curve method was used for the most promising combination to further evaluate the synergetic effects. RESULTS: nicardipine showed additive effect with fluconazole against fluconazole-resistant and fluconazole-susceptible-dose-dependent strains (DSY565 and CBS138) known to express efflux pumps but not against fluconazole-sensitive strains...
April 14, 2018: Journal of Global Antimicrobial Resistance
Mariana Papalia, Germán Traglia, Melina Ruggiero, Marisa Almuzara, Carlos Vay, Gabriel Gutkind, Soledad María Ramírez, Marcela Radice
OBJECTIVES: The aim of this study was to characterize OXA-258 variants and other features that may contribute to the carbapenem resistant in Achromobacter ruhlandii. METHODS: Kinetic parameters for purified OXA-258a and OXA-258b were determined measuring the rate of hydrolysis of a representative group of antibiotics. Whole-genome shotgun sequencing was performed on A. ruhlandii 38 (producing OXA-258a) and A. ruhlandii 319 (producing OXA-258b) and in silico analysis of antimicrobial resistant determinants was conducted...
April 9, 2018: Journal of Global Antimicrobial Resistance
Vijaya Bharathi Srinivasan, Govindan Rajamohan
In this study, we present the genome sequence of Serratia marcescens SM03, recovered from a human gut in India. The final assembly consists of 26 scaffolds (4620 coding DNA sequences, 5.08 Mb, 59.6% G + C ratio) and 79 tRNA genes. Analysis identified novel genes associated with lactose utilization, virulence, P-loop GTPases involved in urease production, CFA/I fimbriae apparatus and Yersinia - type CRISPR proteins. Antibiotic susceptibility testing indicated drug tolerant phenotype and inhibition assays demonstrated involvement of extrusion in resistance...
April 5, 2018: Genomics
Cheng-Yu Tsai, Si Sun, Hongying Zhang, Andrea Local, Yongxuan Su, Larry A Gross, William G Rice, Stephen B Howell
APTO-253 is a small molecule with anti-proliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]...
April 6, 2018: Molecular Cancer Therapeutics
Fabian Lentz, Norbert Reiling, Ana Martins, Joseph Molnár, Andreas Hilgeroth
The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms...
April 4, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Camila B Mendes-Silverio, Caroline H Lescano, Tiago Zaminelli, Carolina Sollon, Gabriel F Anhê, Edson Antunes, Fabíola Z Mónica
The intracellular levels of cyclic GMP are controlled by its rate of formation through nitric oxide-mediated stimulation of soluble guanylate cyclase (sGC) and its degradation by phosphodiesterases. Multidrug resistance protein 4 (MRP4) expressed in human platelets pumps cyclic nucleotides out of cells. In search for new antiplatelet strategies, we tested the hypothesis that sGC activation concomitant with MRP4 inhibition confers higher antiplatelet efficacy compared with monotherapy alone. This study was undertaken to investigate the pharmacological association of the sGC activator BAY 60-2770 with the MRP4 inhibitor MK571 on human washed platelets...
March 29, 2018: Biochemical Pharmacology
Gaurav Raj Dwivedi, Anupam Maurya, Dharmendra Kumar Yadav, Vigyasa Singh, Feroz Khan, Mahendra Kumar Gupta, Mastan Singh, Mahendra P Darokar, Santosh Kumar Srivastava
The emergence of multidrug resistance (MDR) in Gram negative bacteria (GNB) and lack of novel classes of antibacterial agents have raised an immediate need to identify antibacterial agents, which can reverse the phenomenon of MDR. The purpose of present study was to evaluate synergy potential and understanding the drug resistance reversal mechanism of chanoclavine isolated from Ipomoea muricata against the multidrug resistant clinical isolate of Escherichia coli (MDREC). Although chanoclavine did not show antibacterial activity of its own, but in combination, it could reduce the minimum inhibitory concentration (MIC) of tetracycline (TET) up to 16 folds...
March 29, 2018: Journal of Biomolecular Structure & Dynamics
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