Abstract:
:Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on β-d-2'-C-methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2'-C-methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2'-C-methyl-DAPN-TP, behaves as an adenosine base analog. In vitro assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite in vivo Finally, we found that although both 2'-C-methyl-GTP and 2'-C-methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT) in vitro, DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2'-C-methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2'-C-methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Ehteshami M,Tao S,Ozturk T,Zhou L,Cho JH,Zhang H,Amiralaei S,Shelton JR,Lu X,Khalil A,Domaoal RA,Stanton RA,Suesserman JE,Lin B,Lee SS,Amblard F,Whitaker T,Coats SJ,Schinazi RFdoi
10.1128/AAC.00318-16subject
Has Abstractpub_date
2016-07-22 00:00:00pages
4659-69issue
8eissn
0066-4804issn
1098-6596pii
AAC.00318-16journal_volume
60pub_type
杂志文章abstract::The prophylactic efficacy of 17C91, a carbamate prodrug of atovaquone (ATQ), was investigated in a severe combined immunodeficient mouse model of Pneumocystis carinii pneumonia (PCP). At an oral dosage equivalent to 100 mg of ATQ per kg of body weight per day, 17C91 protected 9 of 10 mice from PCP and had a prophylact...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.10.2217
更新日期:1995-10-01 00:00:00
abstract::In a crossover study, single doses of netilmicin and gentamicin were administered intramuscularly, each at 1.0 and 2.5 mg/kg. The serum concentrations, analyzed by a two-compartment open model with a first-order absorption, indicated that the pharmacokinetics of the drugs are essentially the same. Both drugs were rapi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1128/aac.17.2.184
更新日期:1980-02-01 00:00:00
abstract::The present study demonstrates the in vitro effectiveness of the macrolide rokitamycin and the phenothiazine compound chlorpromazine against Acanthamoeba castellanii. Growth curve evaluations revealed that both drugs inhibit trophozoite growth in dose- and time-dependent ways. The effects of both drugs when they were ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.48.12.4520-4527.2004
更新日期:2004-12-01 00:00:00
abstract::Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2',3'-dideoxycytidine; n = 4) or BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by h...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.9.2174
更新日期:1998-09-01 00:00:00
abstract::Diabetic foot ulcer treatment currently focuses on targeting bacterial biofilms, while dismissing fungi. To investigate this, we used an in vitro biofilm model containing bacteria and fungi, reflective of the wound environment, to test the impact of antimicrobials. Here we showed that while monotreatment approaches in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00672-17
更新日期:2017-08-24 00:00:00
abstract::The therapeutic activity of ciprofloxacin, enoxacin, and ofloxacin was evaluated in guinea pigs with acute and chronic experimental Pseudomonas aeruginosa pneumonia. Intratracheal instillations of P. aeruginosa resulted in fatal pneumonia in all untreated animals within 36 h. Among treatment groups (80 mg/kg [body wei...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.29.3.395
更新日期:1986-03-01 00:00:00
abstract::The methionyl-tRNA synthetase (MetRS) is a novel drug target for the protozoan pathogen Giardia intestinalis. This protist contains a single MetRS that is distinct from the human cytoplasmic MetRS. A panel of MetRS inhibitors was tested against recombinant Giardia MetRS, Giardia trophozoites, and mammalian cell lines....
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01573-15
更新日期:2015-11-01 00:00:00
abstract::Tigecycline is a glycylcycline with activity against Enterobacteriaceae, including multidrug-resistant isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile o...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01678-08
更新日期:2009-07-01 00:00:00
abstract::Actinobacillus actinomycetemcomitans, a pathogen associated with aggressive periodontitis, resists phagocytic killing by polymorphonuclear leukocytes (PMNs). It is susceptible to ciprofloxacin, which PMNs actively accumulate. This study tested the hypothesis that ciprofloxacin-loaded PMNs are more effective at killing...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.6.1980-1984.2002
更新日期:2002-06-01 00:00:00
abstract::Azole antifungal resistance in Aspergillus fumigatus is a worldwide concern. As in most public hospitals in Brazil, antifungal susceptibility tests are not routinely performed for filamentous fungi at our institution. A 4-year retrospective azole antifungal resistance screening revealed two azole-resistant A. fumigatu...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02059-19
更新日期:2020-02-21 00:00:00
abstract::We examined the influences of different pH levels and three different buffers on flucytosine activity against 12 isolates of Candida albicans in two synthetic media, yeast nitrogen base (YNB) and synthetic amino acid medium-fungal (SAAMF), using broth dilution techniques and measuring the endpoints of visual MICs and ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.26.3.364
更新日期:1984-09-01 00:00:00
abstract::Mycobacteroides abscessus (Mab) is an opportunistic environmental pathogen that can cause chronic pulmonary disease in the setting of structural lung conditions such as bronchiectasis, COPD and cystic fibrosis. These infections are often incurable and associated with rapid lung function decline. Mab is naturally resis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02545-20
更新日期:2020-12-23 00:00:00
abstract::The biological signal molecule nitric oxide (NO) was found to induce biofilm dispersal across a range of bacterial species, which led to its consideration for therapeutic strategies to treat biofilms and biofilm-related infections. However, biofilms are often not completely dispersed after exposure to NO. To better un...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01832-17
更新日期:2018-02-23 00:00:00
abstract::Gatifloxacin is an 8-methoxy fluoroquinolone effective against a broad spectrum of pathogens common in pediatric infections. The safety and pharmacokinetics of a single dose of gatifloxacin were studied in pediatric patients from 6 months to 16 years of age. Seventy-six pediatric patients (average age, 6.7 +/- 5.0 yea...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1128/AAC.49.3.1106-1112.2005
更新日期:2005-03-01 00:00:00
abstract::We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species. At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp. At an a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.38.1.144
更新日期:1994-01-01 00:00:00
abstract::Our mutagenesis study has investigated all amino acid mutations in the penicillin-binding domain of PBP 1A from Hungarian pneumococcal isolate 3191 to determine the importance of every mutation in the development of penicillin and cefotaxime resistance. Our data reveal that mutations at amino acid positions 574 to 577...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.1.387-389.2003
更新日期:2003-01-01 00:00:00
abstract::Thirteen normal subjects were given 2, 3, or 4 g of ceftizoxime intravenously in a prospective single-blinded study. Serum and urine concentrations were measured for 48 h. The beta-phase serum half-life ranged from 1.4 to 1.7 h. Approximately 100% of the agent was recovered unchanged in the urine over 48 h. Six of 13 ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.22.5.878
更新日期:1982-11-01 00:00:00
abstract::Minibacterium massiliensis strain CIP107820 is a recently discovered waterborne Gram-negative rod isolated from hospital water samples. It harbors a chromosomally located gene encoding an Ambler class A extended-spectrum β-lactamase termed MIN-1, sharing 56%, 54%, and 51% amino acid identities with β-lactamases LUT-1,...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.06401-11
更新日期:2012-07-01 00:00:00
abstract::The in vitro interactions between amikacin, netilmicin, tobramycin, gentamicin, and various antipseudomonal beta-lactams were studied by the agar dilution checkerboard technique against 30 Pseudomonas aeruginosa strains resistant to all tested antibiotics. Amikacin produced more frequent synergy both at the total and ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.4.534
更新日期:1984-04-01 00:00:00
abstract::Berberine, a quaternary alkaloid, and several of its derivatives were tested for efficacy against Leishmania donovani and Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine was less toxic and more potent than berberine against L. donovani but was not as potent as meglumine antimonate (Glucantim...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.5.918
更新日期:1990-05-01 00:00:00
abstract::We examined the inhibitory activities of 10 polyether antibiotics on human immunodeficiency virus (HIV) type 1. These compounds caused concentration-dependent inhibition of HIV replication in primary infected cultures of human T-lymphoblastoid H9 cells. The ratio of 50% effective concentrations for cellular cytotoxici...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.2.492
更新日期:1992-02-01 00:00:00
abstract::Two group F vibrio organisms have been identified among a collection of vibrio strains isolated from the aquatic environment in Bangladesh. Neither group F strain produced a cholera-like enterotoxin. One of the isolates, BV12, contained an R plasmid conferring resistance to streptomycin and chloramphenicol. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.17.3.512
更新日期:1980-03-01 00:00:00
abstract::beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analog with an unnatural beta-L sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro anti...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.4.920
更新日期:1999-04-01 00:00:00
abstract::The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were c...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.01183-06
更新日期:2007-08-01 00:00:00
abstract::Two hundred clinical isolates of Haemophilus influenzae were tested for tolerance (MBC/MIC greater than or equal to 32) to ampicillin and cefotaxime by broth dilution tests. Of 200 strains, 9 were tolerant to ampicillin, and 10 were tolerant to cefotaxime. Tolerant organisms were identified in both systemic and nonsys...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.28.2.320
更新日期:1985-08-01 00:00:00
abstract::Gentamicin entrapped within stable multilamellar liposomes was used to treat mice after they were infected per os with Salmonella dublin. Of 10 mice, 8 survived after a single intravenous (i.v.) injection of 2 mg of gentamicin liposomes per kg compared with 0 of 10 treated with the same amount of free gentamicin. All ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.2.343
更新日期:1990-02-01 00:00:00
abstract::Biofilm formation mediated by polysaccharide intercellular adhesin (PIA) is the major virulence factor of Staphylococcus epidermidis and is often associated with methicillin resistance. Transposon Tn917 insertions leading to a biofilm-negative phenotype in the biofilm-producing S. epidermidis strain 1457 (mecA-negativ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.1.178-183.2002
更新日期:2002-01-01 00:00:00
abstract::The effects of sub-MICs of certain antibiotics, namely, penicillin G, tetracycline, and trimethoprim-sulfamethoxazole, on the cell surface characteristics and the virulences of two toxigenic isolates of Pasteurella multocida representing capsular types A and D were evaluated. Expression of proteins, in particular, out...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.10.2093
更新日期:1992-10-01 00:00:00
abstract::The antibiotic tolerances of bacterial persisters have been attributed to transient dormancy. While persisters have been observed to be growth inhibited prior to antibiotic exposure, we sought to determine whether such a trait was essential to the phenotype. Furthermore, we sought to provide direct experimental eviden...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00243-13
更新日期:2013-07-01 00:00:00
abstract::Three sizes of inserted regions of DNA (800, 1,000, and 1,500 bp) were shown to be common among class I integrons in unrelated clinical isolates of Enterobacteriaceae from different European hospitals. Sequencing showed that 800-bp inserted regions comprised identical sequences including aacA4, that 1,000-bp inserted ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.3.686
更新日期:1999-03-01 00:00:00