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https://www.readbyqxmd.com/read/28650160/discovery-of-novel-nucleotide-prodrugs-with-improved-potency-against-hcv-variants-carrying-ns5b-s282t-mutation
#1
Le Zhen, Liang Dai, Xiaoan Wen, Lan Yao, Xiaoliang Jin, Xiaowen Yang, Wenfeng Zhao, Sheng-Qi Yu, Haoliang Yuan, Guangji Wang, Hongbin Sun
Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. Based on the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e, 4m (EC50 0...
June 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28646094/immune-mediated-effects-targeting-hepatitis-c-virus-in-a-syngeneic-replicon-cell-transplantation-mouse-model
#2
Sepideh Levander, Fredrik Holmström, Lars Frelin, Gustaf Ahlén, Daniel Rupp, Gang Long, Ralf Bartenschlager, Matti Sällberg
OBJECTIVE: HCV is characterised by its ability to establish chronic infection in hepatocytes and to replicate in the presence of an inflammation. We mimicked this situation in vivo in immune-competent mice by syngeneic transplantation of HCV replicon-containing mouse hepatoma cells. DESIGN: A total of 5 million H-2(b) positive Hep56.1D cells, carrying a subgenomic genotype (gt) 2a replicon (HCV replicon cells) or stably expressing comparable levels of the HCV NS3/4A protease/helicase complex (NS3/4A hepatoma cells), were injected subcutaneously into syngeneic H-2(b)-restricted mice...
June 23, 2017: Gut
https://www.readbyqxmd.com/read/28643490/characterization-of-extended-spectrum-%C3%AE-lactamase-genes-of-shigella-flexneri-isolates-with-fosfomycin-resistance-from-patients-in-china
#3
Yanyan Liu, Yue Cheng, Haifei Yang, Lifen Hu, Jun Cheng, Ying Ye, Jiabin Li
BACKGROUND: The emergence of fosfomycin resistance and extended-spectrum β-lactamase (ESBL) genes is a serious threat to public health and a new challenge in shigellosis treatment. The purpose of this study was to identify fosfomycin resistance and characterize β-lactamase genes in fos-carrying isolates of Shigella flexneri from patients in China. METHODS: A total of 263 S. flexneri isolates were collected from 34 hospitals in the Anhui Province of China during September 2012-September 2015 and screened for fosA3, fosA, and fosC2 by PCR amplification and sequencing...
September 2017: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/28643488/multidrug-resistance-mechanisms-of-carbapenem-resistant-klebsiella-pneumoniae-strains-isolated-in-chongqing-china
#4
Jinrong Yan, Shuli Pu, Xiaojiong Jia, Xiuyu Xu, Shuangshuang Yang, Jing Shi, Shan Sun, Liping Zhang
BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is considered a serious global threat. However, little is known regarding the multidrug resistance (MDR) mechanisms of CRKP. This study investigated the phenotypes and MDR mechanisms of CRKP and identified their clonal characteristics. METHODS: PCR and sequencing were utilized to identify antibiotic resistance determinants. Integron gene cassette arrays were determined by restriction fragment length polymorphism (RFLP) analysis...
September 2017: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/28641531/application-of-alphaviral-vectors-for-immunomodulation-in-cancer-therapy
#5
Anna Zajakina, Karina Spunde, Kenneth Lundstrom
BACKGROUND: The lack of specific and efficient cancer therapies has influenced the development of novel approaches, such as immunotherapy, which from its original application of immunogenic protein delivery has developed into the use of more sophisticated recombinant gene delivery methods to achieve better safety and efficacy profiles. This approach involves viral and non-viral delivery systems. METHODS: Expression vectors have been engineered for alphaviruses, including Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus...
June 21, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28641298/generation-of-a-dna-launched-reporter-replicon-based-on-dengue-virus-type-2-as-a-multipurpose-platform
#6
Jose A Usme-Ciro, Jaime A Lopera, Diego A Alvarez, Luis Enjuanes, Fernando Almazán
No abstract text is available yet for this article.
June 23, 2017: Intervirology
https://www.readbyqxmd.com/read/28637330/occurrence-of-aminoglycoside-modifying-enzymes-ames-among-isolates-of-escherichia-coli-exhibiting-high-levels-of-aminoglycoside-resistance-isolated-from-korean-cattle-farms
#7
Kuastros Mekonnen Belaynehe, Seung Won Shin, Park Hong-Tae, Han Sang Yoo
This study investigated 247 Escherichia coli isolates collected from four cattle farms to characterize aminoglycoside-modifying enzyme (AME) genes, their plasmid replicons and transferability. Out of 247 isolates a high number of isolates (total 202; 81.78%) were found resistant to various antibiotics by disc-diffusion. Of the 247 strains 139 (56.3%) were resistant to streptomycin and other antibiotics resistance followed as tetracycline (12.15%), ampicillin (7%), chloramphenicol (5.7%) and trimethoprim-sulfamethoxazole (0...
June 15, 2017: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/28636348/the-development-of-an-aryloxazole-class-of-hepatitis-c-virus-inhibitors-targeting-the-entry-stage-of-the-viral-replication-cycle
#8
Shanshan He, Kelin Li, Billy Lin, Zonyi Hu, Jingbo Xiao, Xin Hu, Amy Q Wang, Xin Xu, Marc Ferrer, Noel Southall, Wei Zheng, Jeffrey Aubé, Frank J Schoenen, Juan J Marugan, T Jake Liang, Kevin J Frankowski
Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps, such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28631340/insights-into-the-genomic-plasticity-of-pseudomonas-putida-kf715-a-strain-with-unique-biphenyl-utilizing-activity-and-genome-instability-properties
#9
Hikaru Suenaga, Hidehiko Fujihara, Nobutada Kimura, Jun Hirose, Takahito Watanabe, Taiki Futagami, Masatoshi Goto, Jun Shimodaira, Kensuke Furukawa
Pseudomonas putida KF715 exhibits unique properties in both catabolic activity and genome plasticity. Our previous studies revealed that the DNA region containing biphenyl and salycilate metabolism gene clusters (termed the bph-sal element) was frequently deleted and transferred by conjugation to closely related P. putida strains. In this study, we first determined the complete nucleotide sequence of the KF715 genome. Next, to determine the underlying cause of genome plasticity in KF715, we compared the KF715 genome with the genomes of one KF715 defective mutant, two transconjugants, and several P...
June 19, 2017: Environmental Microbiology Reports
https://www.readbyqxmd.com/read/28630129/the-polar-organizing-protein-popz-is-required-for-chromosome-segregation-in-agrobacterium-tumefaciens
#10
Haley M Ehrle, Jacob T Guidry, Rebecca Iacovetto, Anne K Salisbury, D J Sandidge, Grant Bowman
Despite being perceived as relatively simple organisms, many bacteria exhibit an impressive degree of sub-cellular organization. In Caulobacter crescentus, the evolutionarily conserved polar organizing protein PopZ facilitates cytoplasmic organization by recruiting chromosome centromeres and regulatory proteins to the cell poles. Here, we characterize the localization and function of PopZ in Agrobacterium tumefaciens, a genetically related species with distinct anatomy. In this species, we find that PopZ molecules are relocated from the old pole to the new pole in the minutes following cell division...
June 19, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28629711/single-step-construction-of-a-picornavirus-replicon-rna-with-precise-ends
#11
Qing Xiong, Yuya Wang, Bingyu Xie, Xinyi Pei, Yihong Peng
A versatile single-step method is described for constructing a picornavirus replicon RNA with precise ends to facilitate improved understanding of viral genome function and mimic native virus replication in host cells as far as possible. The key innovation in this new approach is the use of a bridge primer to both introduce a ribozyme sequence for cis-cleavage of RNA to generate precise 5' ends of EV71 RNA and also mediate overlapping assembly of two fragments. Using an EV71 replicon as a test case, precise ends for the viral replicon were shown to be important for efficient virus replication...
June 16, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28626533/synthesis-and-anti-hcv-activity-of-a-novel-2-3-dideoxy-2-%C3%AE-fluoro-2-%C3%AE-c-methyl-guanosine-phosphoramidate-prodrug
#12
Wenquan Yu, Ertong Li, Zhigang Lv, Ke Liu, Xiaohe Guo, Yuan Liu, Junbiao Chang
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28613981/detection-of-new-delhi-metallo-%C3%AE-lactamase-variants-ndm-4-ndm-5-and-ndm-7-in-enterobacter-aerogenes-isolated-from-a-neonatal-intensive-care-unit-of-a-north-india-hospital-a-first-report
#13
Nayeem Ahmad, Syed Manazir Ali, Asad U Khan
A total 402 Enterobacteriaceae isolates were recovered from blood and rectal swabs of 1,000 infants admitted to the Neonatal Intensive Care Unit (NICU) of the Jawaharlal Medical College and Hospital Aligarh, India. Carbapenamase producers were determined by Carba NP phenotype biochemical assay. Out of 402 isolates, it was the first time three of the isolates were identified as Enterobacter aerogenes carrying blaNDM-4, blaNDM-5, and blaNDM-7 genes. These genes were identified by polymerase chain reaction (PCR) and sequence analysis...
June 14, 2017: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/28609784/genome-wide-profiling-of-s-mar-based-replicon-contact-sites
#14
Claudia Hagedorn, Andreas Gogol-Döring, Sabrina Schreiber, Jörg T Epplen, Hans J Lipps
Autonomously replicating vectors represent a simple and versatile model system for genetic modifications, but their localization in the nucleus and effect on endogenous gene expression is largely unknown. Using circular chromosome conformation capture we mapped genomic contact sites of S/MAR-based replicons in HeLa cells. The influence of cis-active sequences on genomic localization was assessed using replicons containing either an insulator sequence or an intron. While the original and the insulator-containing replicons displayed distinct contact sites, the intron-containing replicon showed a rather broad genomic contact pattern...
June 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28607390/west-nile-virus-infectious-replicon-particles-generated-using-a-packaging-restricted-cell-line-is-a-safe-reporter-system
#15
Wei Li, Le Ma, Li-Ping Guo, Xiao-Lei Wang, Jing-Wei Zhang, Zhi-Gao Bu, Rong-Hong Hua
West Nile virus (WNV) is a neurotropic pathogen which causes zoonotic disease in humans. Recently, there have been an increasing number of infected cases and there are no clinically approved vaccines or effective drugs to treat WNV infections in humans. The purpose of this study was to facilitate vaccine and antiviral drug discovery by developing a packaging cell line-restricted WNV infectious replicon particle system. We constructed a DNA-based WNV replicon lacking the C-prM-E coding region and replaced it with a GFP coding sequence...
June 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28604274/routine-prophylactic-antimicrobial-use-is-associated-with-increased-phenotypic-and-genotypic-resistance-in-commensal-escherichia-coli-isolates-recovered-from-healthy-fattening-pigs-on-farms-in-thailand
#16
Kittitat Lugsomya, Thanitta Chatsuwan, Waree Niyomtham, Padet Tummaruk, David J Hampson, Nuvee Prapasarakul
This study examined antimicrobial resistance (AMR) profiles in commensal Escherichia coli derived from healthy fattening pigs in Thai farms that used prophylactic antimicrobials (in-feed tiamulin fumarate and amoxicillin) [PAs], therapeutic antimicrobials (injectable enrofloxacin or gentamicin) [TAs], or no antimicrobials [NAs]. Commensal E. coli were used as a proxy for overall AMR on the farms. There was a high level of multidrug resistance in all three categories of farm, with isolates showing resistance to β-lactams (amoxicillin, ampicillin, and piperacillin) and tetracyclines (tetracycline), and commonly possessing tetA, blaTEM, and plasmid replicons FIB and F...
June 12, 2017: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/28602519/diversity-of-plasmids-harboring-blacmy-2-in-multidrug-resistant-escherichia-coli-isolated-from-poultry-in-brazil
#17
Joseane Cristina Ferreira, Rafael Antonio Casarin Penha Filho, Leonardo Neves Andrade, Angelo Berchieri Junior, Ana Lúcia Costa Darini
Multidrug-resistance (MDR) has been increasingly reported in Gram-negative bacteria from the intestinal microbiota, environment and food-producing animals. Resistance plasmids able to harbor different transposable elements are capable to mobilize antimicrobial resistance genes and transfer to other bacterial hosts. Plasmids carrying blaCMY are frequently associated with MDR. The present study assessed the presence of plasmid-encoded ampC genes (blacmy, blamox, blafox, blalat, blaact, blamir, bladha, blamor) in commensal E...
May 3, 2017: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28583548/impact-of-steroids-on-natural-killer-cells-against-cytotoxicity-and-hepatitis-c-virus-replication
#18
M Ohira, S Nishida, P Tryphonopoulos, P Ruiz, H Ohdan, A G Tzakis
BACKGROUND: Natural killer (NK) cells play important roles in killing tumor and virus-infected cells. Immunosuppression used after organ transplantation is thought to increase the risk of tumor recurrence and viral infections. However, the effect of immunosuppressive drugs on NK cells has not yet been clearly established. Therefore, we examined the effect of immunosuppression on NK cells. METHODS: NK cells were cultured for 7 days in the presence of interleukin-2 (100 U/mL) with or without the following immunosuppressive drugs: tacrolimus, cyclosporine A, corticosteroid (methylprednisolone [MP]), mycophenolate mofetil, and rapamycin...
June 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28580714/marine-alkaloid-oroidin-analogues-with-antiviral-potential-a-novel-class-of-synthetic-compounds-targeting-the-cellular-chaperone-hsp90
#19
Katja-Emilia Lillsunde, Tihomir Tomašič, Danijel Kikelj, Päivi Tammela
Marine organisms and their metabolites are a diverse source of scaffolds for potential pharmacological molecular probes and, less frequently, for pharmaceutical lead compounds. In this study, 157 synthetic analogues of marine sponge-derived alkaloids clathrodin and oroidin were screened against replicon models of two RNA viruses, hepatitis C (HCV) and Chikungunya virus (CHIKV) as part of a larger screening project. Four compounds were found to selectively inhibit the HCV replicon (IC50 1.6-4.6 μM). These belong to the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole class of compounds originally designed to target the ATP-binding site of bacterial DNA gyrase...
June 5, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28566716/glycogen-synthase-kinase-3%C3%AE-inhibitors-prevent-hepatitis-c-virus-release-assembly-through-perturbation-of-lipid-metabolism
#20
Mohammed A Sarhan, Mohamed S Abdel-Hakeem, Andrew L Mason, D Lorne Tyrrell, Michael Houghton
Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-β inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses...
May 31, 2017: Scientific Reports
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