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Efflux pumps

Angharad E Green, Alejandro Amézquita, Yvan Le-Marc, Matthew J Bull, Thomas R Connor, Eshwar Mahenthiralingam
Pseudomonas aeruginosa (P. aeruginosa) is a common contaminant associated with product recalls in the home and personal care (HPC) industry. Preservation systems are used to prevent spoilage and protect consumers, but greater knowledge is needed of preservative resistance mechanisms used by P. aeruginosa contaminants. We aimed to identify genetic pathways associated with preservative exposure by using an industrial P. aeruginosa strain and implementing RNA-Seq to understand gene expression changes in response to industry relevant conditions...
March 14, 2018: FEMS Microbiology Letters
Jane Hawkey, David B Ascher, Louise M Judd, Ryan R Wick, Xenia Kostoulias, Heather Cleland, Denis W Spelman, Alex Padiglione, Anton Y Peleg, Kathryn E Holt
Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenem resistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing...
March 16, 2018: Microbial Genomics
Jacob B Williams, Clara G Buchanan, William G Pitt
Background - Patients undergoing chemotherapy can develop resistance not only to the administered drug, but also to many other unrelated types of drugs, a phenomenon known as multidrug resistance. One of the most common mechanisms of multidrug resistance is an elevated expression of drug efflux pumps. Co-delivery of an efflux pump inhibitor with a chemotherapeutic can increase the killing of multidrug resistant cancer cells. Objective - Our hypothesis was that delivering doxorubicin directly to the cytosol of multidrug resistant cancer cells via a folate-targeted liposome loaded with a perfluoropentane emulsion droplet and doxorubicin (folated eLipoDox), along with the delivery of verapamil to block the efflux pumps will prove to be more effective at killing multidrug resistant cancer cells compared to conventional drug delivery...
March 16, 2018: Pharmaceutical Nanotechnology
Ronald Domalaon, Temilolu Idowu, George G Zhanel, Frank Schweizer
The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades...
April 2018: Clinical Microbiology Reviews
Kinh Van Nguyen, Trung Vu Nguyen, Hang Thi Thuy Nguyen, Duyet Van Le
Introduction: Pseudomonas aeruginosa has many mechanisms of resistance to fluoroquinolones. The main mechanism is to change the effect of two enzymes that open the DNA helix - the enzyme DNA gyrase ( gyrA ) and the topoisomerase IV ( parC ). In addition, mutations that render the MexAB-oprM pump ( mexR ) dysfunctional, leading to its overexpression, also enhance resistance to fluoroquinolones. In this study, we aim to detect point mutations of gyrA , parC , and mexR genes that are predicted to be associated with fluoroquinolone resistance in 141 fluoroquinolone-resistant clinical isolates of P...
2018: Infection and Drug Resistance
Ana Lopes, Eva Martins, Renata Silva, Madalena M M Pinto, Fernando Remião, Emília Sousa, Carla Fernandes
Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1 - 8 , studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells...
March 10, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Paulo Juarez, Isabelle Broutin, Christophe Bordi, Patrick Plésiat, Catherine Llanes
When overproduced, the multidrug efflux system MexEF-OprN increases resistance of Pseudomonas aeruginosa to fluoroquinolones, chloramphenicol and trimethoprim. In this work, we demonstrate that gain-of-function mutations in regulatory gene mexT result in oligomerization of LysR regulator MexT, in constitutive upregulation of the efflux pump and increased resistance in clinical isolates.
March 12, 2018: Antimicrobial Agents and Chemotherapy
Chenlang Liu, Fangnan Yu, Qingshu Liu, Xiaoying Bian, Shengbiao Hu, Huansheng Yang, Yulong Yin, Yuezhong Li, Yuemao Shen, Liqiu Xia, Qiang Tu, Youming Zhang
Transporter engineering has been shown to be a positive approach for enhancing natural product titers in microbial cell factories by expelling target compounds out of feasible hosts. In this work, two multidrug efflux pumps, Orf14 and Orf3, were modulated in the epothilone production strain Burkholderia DSM7029::Tn5-km-epo (named G32) via Red/ET engineering to increase heterologous polyketide epothilone yields. Compared with the prior G32 strain, the total production of several epothilones in the G32::orf14-orf3 mutant was meaningfully doubled according to high-performance liquid chromatography-mass spectrometer (HPLC-MS) analysis...
February 26, 2018: FEMS Microbiology Letters
Mary K Phillips-Jones, Stephen E Harding
In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics-the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins...
March 10, 2018: Biophysical Reviews
William Gustavo Lima, Mara Cristina Alves, Waleska Stephanie Cruz, Magna Cristina Paiva
Acinetobacter baumannii is an opportunistic pathogen associated with nosocomial and community infections of great clinical relevance. Its ability to rapidly develop resistance to antimicrobials, especially carbapenems, has re-boosted the prescription and use of polymyxins. However, the emergence of strains resistant to these antimicrobials is becoming a critical issue in several regions of the world because very few of currently available antibiotics are effective in these cases. This review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A...
March 9, 2018: European Journal of Clinical Microbiology & Infectious Diseases
Cátia F Gonçalves, Catarina C Pacheco, Paula Tamagnini, Paulo Oliveira
Cyanobacteria were the first organisms ever to perform oxygenic photosynthesis and still significantly contribute to primary production on a global scale. To assure the proper functioning of their primary metabolism and cell homeostasis, cyanobacteria must rely on efficient transport systems to cross their multilayered cell envelope. However, cyanobacterial secretion mechanisms remain largely unknown. Here, we report on the identification of 11 putative inner membrane translocase components of TolC-mediated secretion in the unicellular cyanobacterium Synechocystis sp...
March 9, 2018: Environmental Microbiology
Antonin Dréan, Shai Rosenberg, François-Xavier Lejeune, Larissa Goli, Aravindan Arun Nadaradjane, Jérémy Guehennec, Charlotte Schmitt, Maïté Verreault, Franck Bielle, Karima Mokhtari, Sanson Marc, Alexandre Carpentier, Delattre Jean-Yves, Ahmed Idbaih
ATP-binding cassette transporters (ABC transporters) regulate traffic of multiple compounds, including chemotherapeutic agents, through biological membranes. They are expressed by multiple cell types and have been implicated in the drug resistance of some cancer cells. Despite significant research in ABC transporters in the context of many diseases, little is known about their expression and clinical value in glioblastoma (GBM). We analyzed expression of 49 ABC transporters in both commercial and patient-derived GBM cell lines as well as from 51 human GBM tumor biopsies...
March 8, 2018: Journal of Neuro-oncology
Ardeshir Rineh, John B Bremner, Michael R Hamblin, Anthony R Ball, George P Tegos, Michael J Kelso
Resistance of bacteria to antibiotics is a public health concern worldwide due to the increasing failure of standard antibiotic therapies. Antimicrobial photodynamic inactivation (aPDI) is a promising non-antibiotic alternative for treating localized bacterial infections that uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species and kill microbes. Phenothiazinium photosensitizers like methylene blue (MB) and toluidine blue O are hydrophobic cations that are naturally expelled from bacterial cells by multidrug efflux pumps, which reduces their effectiveness...
February 24, 2018: Bioorganic & Medicinal Chemistry Letters
Lijun Song, Romain Merceron, Begoña Gracia, Ainhoa Lucia Quintana, Martijn D P Risseeuw, Fabian Hulpia, Paul Cos, Jose A Ainsa, Hélène Munier-Lehmann, Savvas N Savvides, Serge Van Calenbergh
In recent years thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs we have built upon our previous efforts towards the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and report here the design of a novel series of non-nucleoside inhibitors of MtTMPK that exhibit nanomolar potency...
March 6, 2018: Journal of Medicinal Chemistry
Mitchell P McInerney, Irene Volitakis, Ashley I Bush, William A Banks, Jennifer L Short, Joseph A Nicolazzo
PURPOSE: Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown. METHODS: Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper...
March 5, 2018: Pharmaceutical Research
Sarah G Whaley, Kelly E Caudle, Lucia Simonicova, Qing Zhang, W Scott Moye-Rowley, P David Rogers
The high prevalence of fluconazole resistance among clinical isolates of Candida glabrata has greatly hampered the utility of fluconazole for the treatment of invasive candidiasis. Fluconazole resistance in this yeast is almost exclusively due to activating mutations in the transcription factor Pdr1, which result in upregulation of the ABC transporter genes CDR1 , PDH1 , and SNQ2 and therefore increased fluconazole efflux. However, the regulation of Pdr1 is poorly understood. In order to identify genes that interact with the Pdr1 transcriptional pathway and influence the susceptibility of C...
January 2018: MSphere
Yi-Hsiang Cheng, Tzu-Lung Lin, Yi-Tsung Lin, Jin-Town Wang
Background: Colistin is one of the last-resort antibiotics used to treat carbapenem-resistant Klebsiella pneumoniae infection. Our previous studies indicated that clinical strains encoding CrrB with amino acid substitutions exhibited higher colistin resistance (MICs ≥512 mg/L) than did colistin-resistant strains encoding mutant MgrB, PmrB or PhoQ. Objectives: CrrAB may regulate another unknown mechanism(s) contributing to colistin resistance, besides modifications of LPS with 4-amino-4-deoxy-l-arabinose and phosphoethanolamine...
February 28, 2018: Journal of Antimicrobial Chemotherapy
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
Diego B Nobrega, Sohail Naushad, S Ali Naqvi, Larissa A Z Condas, Vineet Saini, John P Kastelic, Christopher Luby, Jeroen De Buck, Herman W Barkema
Emergence and spread of antimicrobial resistance is a major concern for the dairy industry worldwide. Objectives were to determine: (1) phenotypic and genotypic prevalence of drug-specific resistance for 25 species of non-aureus staphylococci, and (2) associations between presence of resistance determinants and antimicrobial resistance. Broth micro-dilution was used to determine resistance profiles for 1,702 isolates from 89 dairy herds. Additionally, 405 isolates were sequenced to screen for resistance determinants...
2018: Frontiers in Microbiology
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
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