Nonnucleoside inhibitors of norovirus RNA polymerase: scaffolds for rational drug design.


:Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 "lead-like" compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC50s) between 5.0 μM and 9.8 μM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC50s) of 30.1 μM and 71.1 μM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC50s between 2.3 μM and 4.8 μM). The remaining three compounds also reduced MNV replication, although with higher EC50s, ranging from 32 μM to 38 μM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.


Eltahla AA,Lim KL,Eden JS,Kelly AG,Mackenzie JM,White PA




Has Abstract


2014-06-01 00:00:00














  • Thiolated recombinant human tumor necrosis factor-alpha protects against Plasmodium berghei K173-induced experimental cerebral malaria in mice.

    abstract::The introduction of reactive thiol groups in recombinant human tumor necrosis factor (TNF) alpha (rhTNF-alpha) by the reagent succinimidyl-S-acetylthioacetate resulted in the formation of a chemically stabilized rhTNF-alpha trimer (rhTNFalpha-AT; as determined by sodium dodecyl sulfate-polyacrylamide gel electrophores...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Postma NS,Hermsen RC,Crommelin DJ,Eling WM,Zuidema J

    更新日期:1999-05-01 00:00:00

  • In vitro activities of DX-619 and four comparator agents against 376 anaerobic bacterial isolates.

    abstract::The activity of DX-619 was evaluated against 376 anaerobic isolates using the reference CLSI agar dilution method. Overall, 90% of the strains were susceptible to DX-619 at < or =1 microg/ml. It was more active than the other four compounds tested except for meropenem, which showed virtually identical overall activity...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Molitoris D,Väisänen ML,Bolaños M,Finegold SM

    更新日期:2006-05-01 00:00:00

  • A Pilot Study of Chicago Waterways as Reservoirs of Multidrug-Resistant Enterobacteriaceae (MDR-Ent) in a High-Risk Region for Community-Acquired MDR-Ent Infection in Children.

    abstract::Community-acquired multidrug resistant Enterobacteriaceae (MDR-Ent) infections continue to increase in the United States. In prior studies, we identified neighboring regions in Chicago, Illinois, where children have 5 to 6 times greater odds of MDR-Ent infections. To prevent community spread of MDR-Ent, we need to ide...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Logan LK,Zhang L,Green SJ,Dorevitch S,Arango-Argoty GA,Reme K,Garner E,Aldstadt J,Johnson-Walker YJ,Hayden MK,Weinstein RA,Pruden A

    更新日期:2020-03-24 00:00:00

  • Application of quantitative real-time reverse transcription-PCR in assessing drug efficacy against the intracellular pathogen Cryptosporidium parvum in vitro.

    abstract::We report here on a quantitative real-time reverse transcription-PCR (qRT-PCR) assay for assessing drug efficacy against the intracellular pathogen Cryptosporidium parvum. The qRT-PCR assay detects 18S rRNA transcripts from both parasites, that is, the cycle threshold for 18S rRNA from parasites (C(T)([P18S])) and hos...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Cai X,Woods KM,Upton SJ,Zhu G

    更新日期:2005-11-01 00:00:00

  • Activity of DX-619 compared to other agents against viridans group streptococci, Streptococcus bovis, and Cardiobacterium hominis.

    abstract::Against 198 viridans group streptococci, 25 Streptococcus bovis strains, and 5 Cardiobacterium hominis strains, MICs of DX-619, a des-F(6)-quinolone, were between 0.004 and 0.25 microg/ml. These MICs were lower than those of other quinolones (< or = 0.008 to > 32 microg/ml). Beta-lactam MICs were between < or = 0.008 ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Kosowska-Shick K,Smith K,Bogdanovich T,Ednie LM,Jones RN,Appelbaum PC

    更新日期:2006-12-01 00:00:00

  • Antimicrobial activity of ceftaroline-avibactam tested against clinical isolates collected from U.S. Medical Centers in 2010-2011.

    abstract::Ceftaroline-avibactam and comparator agents were tested by the broth microdilution method against 20,089 isolates consecutively collected in 2010 and 2011 from 75 U.S. medical centers. Ceftaroline-avibactam was active against Enterobacteriaceae (4,908 strains; MIC90, 0.25 μg/ml; highest MIC, 4 μg/ml), including merope...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Sader HS,Flamm RK,Jones RN

    更新日期:2013-04-01 00:00:00

  • Determination of an inoculum effect with various cephalosporins among clinical isolates of methicillin-susceptible Staphylococcus aureus.

    abstract::Using 98 clinical methicillin-susceptible Staphylococcus aureus isolates of known beta-lactamase (Bla) type, we found a pronounced inoculum effect for cephalexin (mostly Bla type A and C strains), a mild inoculum effect for cephalothin (especially types B and C), and no inoculum effects for ceftriaxone and cefuroxime....

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Nannini EC,Stryjewski ME,Singh KV,Rude TH,Corey GR,Fowler VG Jr,Murray BE

    更新日期:2010-05-01 00:00:00

  • In vitro activities of daptomycin and other antimicrobial agents against vancomycin-resistant gram-positive bacteria.

    abstract::A comparative evaluation of daptomycin and eight other antimicrobial agents was performed by the agar dilution technique with 56 strains of vancomycin-resistant gram-positive bacteria, including Leuconostoc, Lactobacillus, and Pediococcus spp. Erythromycin, deptomycin, clindamycin, and gentamicin exhibited the greates...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: de la Maza L,Ruoff KL,Ferraro MJ

    更新日期:1989-08-01 00:00:00

  • Effect of subinhibitory concentrations of antibiotics on the adhesion of Streptococcus pyogenes to pharyngeal epithelial cells.

    abstract::The hydrophobicity and charge of the cell surface of M protein-positive (M+) and the less virulent M protein-negative (M-) strains of type 12 Streptococcus pyogenes have been studied, respectively, by hydrophobic interaction chromatography and free zone electrophoresis. The M+ strain had a more hydrophobic and a more ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Tylewska S,Hjertén S,Wadström T

    更新日期:1981-11-01 00:00:00

  • Rapid inversion of the prevalences of macrolide resistance phenotypes paralleled by a diversification of T and emm types among Streptococcus pyogenes in Portugal.

    abstract::In Portugal erythromycin resistance of 26.6% (n = 352) remained constant during 1998 to 2003, however in 1998 the MLS(B) phenotype dominated (85%), whereas in 2003 the M phenotype prevailed (77%). A decline in T12/emm22 MLS(B) isolates could partially explain the drop in this phenotype, but the rise of the M phenotype...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Silva-Costa C,Ramirez M,Melo-Cristino J,Portuguese Surveillance Group for the Study of Respiratory Pathogens.

    更新日期:2005-05-01 00:00:00

  • Monodrug efficacies of sulfonamides in prophylaxis for Pneumocystis carinii pneumonia.

    abstract::A remarkably high rate of adverse events is associated with the use of trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus type 1 infection. We examined the efficacies of sulfonamides alone in the prevention of Pneumocystis carinii pneumonitis, with the assumption that at least some of the adve...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Hughes WT,Killmar J

    更新日期:1996-04-01 00:00:00

  • Distribution of tet(H) among Pasteurella isolates from the United States and Canada.

    abstract::Tetracycline-resistant isolates of Pasteurella multocida and Pasteurella haemolytica obtained from various locations in the United States and Canada were studied to determine the distribution of the tet(H) gene. Of the 31 isolates examined, 25 were found to contain the tet(H) gene. Chromosomal or plasmid DNA obtained ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Hansen LM,Blanchard PC,Hirsh DC

    更新日期:1996-06-01 00:00:00

  • Itraconazole-amphotericin B antagonism in Aspergillus fumigatus: an E-test-based strategy.

    abstract::We examined an E-test-based strategy for testing the combination of itraconazole and amphotericin B, the latter given either sequentially or concomitantly, in isolates of Aspergillus fumigatus. An antagonistic interaction between the two drugs was noted, especially with the sequential administration of amphotericin B....

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Kontoyiannis DP,Lewis RE,Sagar N,May G,Prince RA,Rolston KV

    更新日期:2000-10-01 00:00:00

  • Health care-associated pneumonia and community-acquired pneumonia: a single-center experience.

    abstract::Pneumonia occurring outside of the hospital setting has traditionally been categorized as community-acquired pneumonia (CAP). However, when pneumonia is associated with health care risk factors (prior hospitalization, dialysis, residing in a nursing home, immunocompromised state), it is now more appropriately classifi...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Micek ST,Kollef KE,Reichley RM,Roubinian N,Kollef MH

    更新日期:2007-10-01 00:00:00

  • Analysis of embCAB mutations associated with ethambutol resistance in multidrug-resistant mycobacterium tuberculosis isolates from China.

    abstract::Ethambutol (EMB) plays a pivotal role in the chemotherapy of drug-resistant tuberculosis (TB), including multidrug-resistant tuberculosis (MDR-TB). Resistance to EMB is considered to be caused by mutations in the embCAB operon (embC, embA, and embB). In this study, we analyzed the embCAB mutations among 139 MDR-TB iso...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Zhao LL,Sun Q,Liu HC,Wu XC,Xiao TY,Zhao XQ,Li GL,Jiang Y,Zeng CY,Wan KL

    更新日期:2015-04-01 00:00:00

  • Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients.

    abstract::Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfon...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Boisson M,Jacobs M,Grégoire N,Gobin P,Marchand S,Couet W,Mimoz O

    更新日期:2014-12-01 00:00:00

  • In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against chlamydia.

    abstract::The in vitro and in vivo activities of azithromycin against chlamydia were investigated. The MIC of azithromycin for five standard strains of different species of chlamydia and six wild-type strains of Chlamydia pneumoniae was 0.125 microgram/ml, which was superior to that of erythromycin but inferior to those of clar...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Niki Y,Kimura M,Miyashita N,Soejima R

    更新日期:1994-10-01 00:00:00

  • In vitro synergism observed with azithromycin, clarithromycin, minocycline, or tigecycline in association with antifungal agents against Pythium insidiosum.

    abstract::We describe here the in vitro activities of azithromycin, clarithromycin, minocycline, or tigecycline alone and in combination with amphotericin B, itraconazole, terbinafine, voriconazole, anidulafungin, caspofungin, or micafungin against 30 isolates of the oomycete Pythium insidiosum. The assays were based on the CLS...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Jesus FP,Ferreiro L,Loreto ÉS,Pilotto MB,Ludwig A,Bizzi K,Tondolo JS,Zanette RA,Alves SH,Santurio JM

    更新日期:2014-09-01 00:00:00

  • Susceptibilities to levofloxacin in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from children: results from 2000-2001 and 2001-2002 TRUST studies in the United States.

    abstract::Among respiratory tract isolates of Streptococcus pneumoniae from children, resistance to penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (SXT) increases on an annual basis. Pediatric patients who do not respond to conventional therapy for respiratory tract infections someday may be treated ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Karlowsky JA,Thornsberry C,Critchley IA,Jones ME,Evangelista AT,Noel GJ,Sahm DF

    更新日期:2003-06-01 00:00:00

  • In vitro activity of Bay v 3522, a new cephalosporin, compared with activities of other agents.

    abstract::The in vitro activity of Bay v 3522, a new aminobenzothiazol cephem, was compared with those of other oral beta-lactams. Bay v 3522 displayed high activity against Staphylococcus spp. (MICs for 90% of strains tested [MIC90S], 0.5 micrograms/ml), Streptococcus pneumoniae (MIC90, 0.06 micrograms/ml), and Haemophilus inf...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Wise R,Andrews JM,Ashby JP,Thornber D

    更新日期:1990-05-01 00:00:00

  • Polycation binding to isolated lipopolysaccharide from antibiotic-hypersusceptible mutant strains of Escherichia coli.

    abstract::Lipopolysaccharide (LPS) samples isolated from a parent and two antibiotic-hypersusceptible mutant strains of Escherichia coli were analyzed for polycation affinity and level of binding. Purified salts of the LPSs from the parent strain, UB1005, and from one of the mutant strains, DC1, bound similar amounts of sodium ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Rocque WJ,Fesik SW,Haug A,McGroarty EJ

    更新日期:1988-03-01 00:00:00

  • Biochemical properties of beta-lactamase produced by Legionella gormanii.

    abstract::beta-Lactamase was purified from a strain of Legionella gormanii. The molecular weight of the purified enzyme was 25,000, and its isoelectric point was 10.5. The enzyme hydrolyzed oxyiminocephalosporins, cephamycins, penicillins, and imipenem. The enzyme activity was inhibited by EDTA, Hg2+, and Cu2+, but not by clavu...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Fujii T,Sato K,Miyata K,Inoue M,Mitsuhashi S

    更新日期:1986-05-01 00:00:00

  • Interaction of Streptococcus pneumoniae and Moraxella catarrhalis: investigation of the indirect pathogenic role of beta-lactamase-producing moraxellae by use of a continuous-culture biofilm system.

    abstract::The majority of clinical isolates of Moraxella catarrhalis produce beta-lactamase. The role of this enzyme in the phenomenon of indirect pathogenicity, in which a true pathogen such as Streptococcus pneumoniae is protected from the action of certain beta-lactam antibiotics, is well recognized. By using a simple contin...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Budhani RK,Struthers JK

    更新日期:1998-10-01 00:00:00

  • Kinetics of the Interaction between BAL29880 and LK157 and the Class C β-Lactamase CHE-1.

    abstract::The chromosome-encoded class C β-lactamase CHE-1 produced by Enterobacter cloacae exhibits a lower sensitivity to avibactam than the P99 enzyme from which it is derived by a 6-residue deletion in the H-10 helix. In the present study, we investigated the sensitivity of CHE-1 to two other β-lactamase inhibitors: LK-157 ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Fernea A,Galleni M,Frère JM

    更新日期:2016-01-04 00:00:00

  • Comparative evaluation of ciprofloxacin, enoxacin, and ofloxacin in experimental Pseudomonas aeruginosa pneumonia.

    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


    authors: Kemmerich B,Small GJ,Pennington JE

    更新日期:1986-03-01 00:00:00

  • Antimicrobial activities of amine- and guanidine-functionalized cholic acid derivatives.

    abstract::Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Li C,Lewis MR,Gilbert AB,Noel MD,Scoville DH,Allman GW,Savage PB

    更新日期:1999-06-01 00:00:00

  • Animal and human multidrug-resistant, cephalosporin-resistant salmonella isolates expressing a plasmid-mediated CMY-2 AmpC beta-lactamase.

    abstract::Salmonella spp. are important food-borne pathogens that are demonstrating increasing antimicrobial resistance rates in isolates obtained from food animals and humans. In this study, 10 multidrug-resistant, cephalosporin-resistant Salmonella isolates from bovine, porcine, and human sources from a single geographic regi...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Winokur PL,Brueggemann A,DeSalvo DL,Hoffmann L,Apley MD,Uhlenhopp EK,Pfaller MA,Doern GV

    更新日期:2000-10-01 00:00:00

  • Activity of a new liposomal formulation of amphotericin B against two strains of Leishmania infantum in a murine model.

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    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Paul M,Durand R,Fessi H,Rivollet D,Houin R,Astier A,Deniau M

    更新日期:1997-08-01 00:00:00

  • Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice.

    abstract::Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC)...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Guiton PS,Cusumano CK,Kline KA,Dodson KW,Han Z,Janetka JW,Henderson JP,Caparon MG,Hultgren SJ

    更新日期:2012-09-01 00:00:00

  • Extended-spectrum properties of CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase.

    abstract::CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase, was derived by mutagenesis. The hydrolytic efficiency of CMY-30 against expanded-spectrum cephalosporins was higher than that of CMY-2 due to increased k(cat) values. Findings indicate a role of the Omega loop residue 211 in determining the substrate specificities ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章


    authors: Kotsakis SD,Papagiannitsis CC,Tzelepi E,Tzouvelekis LS,Miriagou V

    更新日期:2009-08-01 00:00:00