Abstract:
:The exogenous control of hepatitis C virus (HCV) replication can be mediated through the inhibition of the RNA-dependent RNA polymerase (RdRp) activity of NS5B. Small-molecule inhibitors of NS5B include nucleoside and nonnucleoside analogs. Here, we report the discovery of a novel class of HCV polymerase nonnucleoside inhibitors, 1,5-benzodiazepines (1,5-BZDs), identified by high-throughput screening of a library of small molecules. A fluorescence-quenching assay and X-ray crystallography revealed that 1,5-BZD 4a bound stereospecifically to NS5B next to the catalytic site. When introduced into replicons, mutations known to confer resistance against chemotypes that bind at this site were detrimental to inhibition by 1,5-BZD 7a. Using a panel of enzyme isolates that covered genotypes 1 to 6, we showed that compound 4a inhibited genotype 1 only. In mechanistic studies, 4a was found to inhibit the RdRp activity of NS5B noncompetitively with GTP and to inhibit the formation of the first phosphodiester bond during the polymerization cycle. The specificity for the HCV target was evaluated by profiling the 1,5-BZDs against other viral and human polymerases, as well as BZD receptors.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Nyanguile O,Pauwels F,Van den Broeck W,Boutton CW,Quirynen L,Ivens T,van der Helm L,Vandercruyssen G,Mostmans W,Delouvroy F,Dehertogh P,Cummings MD,Bonfanti JF,Simmen KA,Raboisson Pdoi
10.1128/AAC.00669-08subject
Has Abstractpub_date
2008-12-01 00:00:00pages
4420-31issue
12eissn
0066-4804issn
1098-6596pii
AAC.00669-08journal_volume
52pub_type
杂志文章abstract::Enterococcus faecalis strain WCH9 displays a moderate level of resistance to vancomycin (MIC = 16 microgram/ml) and full susceptibility to teicoplanin but is negative by PCR analysis using primers specific for all known enterococcal vancomycin resistance genotypes (vanA, vanB, vanC, vanD, and vanE). We have isolated a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.11.3224-3228.2000
更新日期:2000-11-01 00:00:00
abstract::MCC-478 is a newly synthesized 2-amino-6-arylthio-9-phosphonomethoxyethylpurine bis(2,2,2-trifluoroethyl) ester derivative. MCC-478 showed a substantially higher (ca. 80-fold) anti-hepatitis B virus (HBV) activity than that of lamivudine, despite no significant anti-human immunodeficiency virus activity. Since the bis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.9.2872-2877.2002
更新日期:2002-09-01 00:00:00
abstract::A series of quaternary ammonium compounds that are esters of betaine and fatty alcohols with hydrocarbon chain lengths of 10 to 18 carbon atoms were tested with respect to antimicrobial activities and rates of hydrolysis. When the tetradecyl derivative was tested against some selected microorganisms, the killing effec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.10.1949
更新日期:1990-10-01 00:00:00
abstract::The only human cathelicidin, the 37-residue peptide LL-37, exhibits antimicrobial activity against both gram-positive and gram-negative bacteria. We studied the ability of several fragments of LL-37, exhibiting different antimicrobial activities, to interact with membranes whose compositions mimic the cytoplasmic memb...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00321-09
更新日期:2009-09-01 00:00:00
abstract::SCY-078 is an orally active antifungal whose target is the β-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00833-17
更新日期:2017-08-24 00:00:00
abstract::Lamivudine [beta-L-(-)-2',3'-dideoxy-3'-thiacytidine] is a potent inhibitor of hepadnavirus replication and is used both to treat chronic hepatitis B virus (HBV) infections and to prevent reinfection of transplanted livers. Unfortunately, lamivudine-resistant HBV variants do arise during prolonged therapy, indicating ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.6.1936-1942.2003
更新日期:2003-06-01 00:00:00
abstract::T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 micro...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.1.30
更新日期:1997-01-01 00:00:00
abstract::An Escherichia coli strain with a plasmidic amikacin resistance has been selected for which the evidence strongly indicates that resistance is mediated by aminoglycoside phosphotransferase [APH(3')-II]: (i) this resistance was coupled with resistance against kanamycin and neomycin; (ii) partially purified APH(3')-II[A...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.20.3.344
更新日期:1981-09-01 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::DNA microarrays were used to analyze Candida glabrata oropharyngeal isolates from seven hematopoietic stem cell transplant recipients whose isolates developed azole resistance while the recipients received fluconazole prophylaxis. Transcriptional profiling of the paired isolates revealed 19 genes upregulated in the ma...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00535-10
更新日期:2010-08-01 00:00:00
abstract::We evaluated MEDI8852, a human IgG1 monoclonal antibody that binds a highly conserved influenza A hemagglutinin stalk epitope, in outpatients with uncomplicated influenza A infection. A total of 126 subjects aged 18 to 65 years were enrolled during the 2015 to 2016 Northern and 2016 Southern Hemisphere seasons. Subjec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.00694-18
更新日期:2018-10-24 00:00:00
abstract::We previously reported the development of a prototype antibiotic sensitivity assay to detect drug-resistant Mycobacterium tuberculosis using infection by mycobacteriophage to create a novel nucleic acid transcript, a surrogate marker of mycobacterial viability, detected by reverse transcriptase PCR (M. C. Mulvey et al...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03135-14
更新日期:2015-01-01 00:00:00
abstract::The survival of three bacterial species and Candida albicans was studied on SPI-ARGENT II. The immediate recovery from silver-impregnated polymer and control polymer (1 cm2) was approximately 10(6) to 10(7) microorganisms. After incubation (37 degreesC) and neutralization of silver with horse serum (5%), surviving org...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.9.2440
更新日期:1998-09-01 00:00:00
abstract::Intranasal inoculation of newborn mice with Herpesvirus hominis (HVH) type 2 provides a model for disseminated herpesvirus infections of human newborn infants. Treatment of this experimental infection with polyinosinic-polycytidylic acid [poly(I:C)] significantly increased the mean survival time and markedly altered t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.7.6.793
更新日期:1975-06-01 00:00:00
abstract::Increasing mobile colistin resistance, mediated by the mcr gene family, in Enterobacteriaceae has become a global concern. Among the 10 reported mcr genes, mcr-8 was first identified in Klebsiella pneumoniae, which could cause severe infections with high mortality. Information about the prevalence and genetic context ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01872-20
更新日期:2020-12-16 00:00:00
abstract::Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoqu...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.04419-14
更新日期:2015-02-01 00:00:00
abstract::Candida albicans, an opportunistic fungus, and Staphylococcus aureus, a bacterial pathogen, are two clinically relevant biofilm-forming microbes responsible for a majority of catheter-related infections, with such infections often resulting in catheter loss and removal. Not only do these pathogens cause a substantial ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01599-12
更新日期:2013-01-01 00:00:00
abstract::The effectiveness of newer macrolides in acute Q fever for 113 patients was recorded. The mean times to defervescence were 2.9 days for doxycycline and 3.3, 3.9, 3.9, and 6.4 days for clarithromycin, roxithromycin, erythromycin, and beta-lactams, respectively (P < 0.01 for macrolides versus beta-lactams). We conclude ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.12.3644-3646.2001
更新日期:2001-12-01 00:00:00
abstract::Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) on the Indian subcontinent. The mechanisms operating in laboratory-generated strains are somewhat known, but the determinants of clinical antimony resistance are not well understood. By utili...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00736-11
更新日期:2012-01-01 00:00:00
abstract::Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exp...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02063-17
更新日期:2018-02-23 00:00:00
abstract::Standard therapy of human visceral leishmaniasis with parenteral pentavalent antimonial agents is generally curative but has the disadvantages of a 28-day treatment course, occasional treatment failures, and toxicity. The antifungal and antileishmanial agent amphotericin B has been complexed with lipids to develop a l...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.9.1978
更新日期:1992-09-01 00:00:00
abstract::A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of great...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00723-07
更新日期:2007-12-01 00:00:00
abstract::Although information about the efficacy and safety experience with caspofungin at 50 mg/m(2) daily is available for children and adolescents, the dosing regimen in infants and toddlers 3 to 24 months of age has yet to be established. We studied the pharmacokinetics and safety of caspofungin at 50 mg/m(2) once daily in...
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.01027-08
更新日期:2009-04-01 00:00:00
abstract::We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaco...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01484-13
更新日期:2013-12-01 00:00:00
abstract::Bacteriophage therapy is a promising alternative treatment to antibiotics, as it has been documented to be efficacious against multidrug-resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, p...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01714-17
更新日期:2018-01-25 00:00:00
abstract::Secondary resistance to azoles in Aspergillus fumigatus isolates from patients taking long-term itraconazole therapy has been described. We studied the acquisition of secondary azole resistance in 20 A. fumigatus isolates with no mutations at codon 54, 98, 138, 220, 432, or 448 in the cyp51A gene. Adjusted conidium in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00301-11
更新日期:2012-01-01 00:00:00
abstract::Unlike mammalian cells, malarial parasites are completely dependent on the de novo pyrimidine pathway and lack the enzymes to salvage preformed pyrimidines. In the present study, first, it is shown that 1843U89, even without polyglutamylation, is a potent folate-based inhibitor of purified malarial parasite thymidylat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.4.1047-1050.2000
更新日期:2000-04-01 00:00:00
abstract::Curcumin, a principal component of turmeric, acts as an immunomodulator regulating the host defenses in response to a diseased condition. The role of curcumin in controlling certain infectious diseases is highly controversial. It is known to alleviate symptoms of Helicobacter pylori infection and exacerbate that of Le...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00496-12
更新日期:2012-11-01 00:00:00
abstract::The biosynthetic gene cluster of the aminocoumarin antibiotic coumermycin A(1) was cloned by screening of a cosmid library of Streptomyces rishiriensis DSM 40489 with heterologous probes from a dTDP-glucose 4,6-dehydratase gene, involved in deoxysugar biosynthesis, and from the aminocoumarin resistance gyrase gene gyr...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.11.3040-3048.2000
更新日期:2000-11-01 00:00:00
abstract::We used the Tn10-encoded Tet repressor, which has a highly specific binding capacity for tetracycline, to probe contacts between the drug and protein by chemical interference studies of the antibiotic. For that purpose, the equilibrium association constants of modified tetracyclines with the Tet repressor and Mg2+ cat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.8.1591
更新日期:1991-08-01 00:00:00