Mechanism of action for respiratory syncytial virus inhibitor RSV604.

Abstract:

:Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children and other high-risk populations. RSV nucleoprotein (N) is essential for virus assembly and replication as part of the viral ribonucleoprotein (RNP) complex. RSV604 was a putative N inhibitor in phase 2 clinical trials whose molecular mechanism of action (MoA) was not well understood. This study investigated the cell line-dependent potency of RSV604 and demonstrated its direct binding to the N protein in vitro, providing the first evidence of direct target engagement for this class of inhibitors reported to date. The affinity of RSV604 N binding was not affected by RSV604 resistance mutations in the N protein. RSV604 engaged in two different MoAs in HeLa cells, inhibiting both RSV RNA synthesis and the infectivity of released virus. The lack of inhibition of viral RNA synthesis in some cell lines explained the cell-type-dependent potency of the inhibitor. RSV604 did not inhibit viral RNA synthesis in the RSV subgenomic replicon cells or in the cell-free RNP assay, suggesting that it might act prior to viral replication complex formation. RSV604 did not alter N protein localization in the infected cells. Taken together, these results provide new insights leading to an understanding of the MoAs of RSV604 and other similar N inhibitors.

authors

Challa S,Scott AD,Yuzhakov O,Zhou Y,Tiong-Yip CL,Gao N,Thresher J,Yu Q

doi

10.1128/AAC.04119-14

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

1080-7

issue

2

eissn

0066-4804

issn

1098-6596

pii

AAC.04119-14

journal_volume

59

pub_type

杂志文章
  • Identification and characterization of the anti-methicillin-resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11.

    abstract::Lysobactor enzymogenes strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously ide...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.05370-11

    authors: Zhang W,Li Y,Qian G,Wang Y,Chen H,Li YZ,Liu F,Shen Y,Du L

    更新日期:2011-12-01 00:00:00

  • NVC-422 inactivates Staphylococcus aureus toxins.

    abstract::Bacterial pathogens have specific virulence factors (e.g., toxins) that contribute significantly to the virulence and infectivity of microorganisms within the human hosts. Virulence factors are molecules expressed by pathogens that enable colonization, immunoevasion, and immunosuppression, obtaining nutrients from the...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01945-12

    authors: Jekle A,Yoon J,Zuck M,Najafi R,Wang L,Shiau T,Francavilla C,Rani SA,Eitzinger C,Nagl M,Anderson M,Debabov D

    更新日期:2013-02-01 00:00:00

  • Genetic elements carrying erm(B) in Streptococcus pyogenes and association with tet(M) tetracycline resistance gene.

    abstract::This study was directed at characterizing the genetic elements carrying the methylase gene erm(B), encoding ribosome modification-mediated resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics, in Streptococcus pyogenes. In this species, erm(B) is responsible for MLS resistance in constitutively ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01484-06

    authors: Brenciani A,Bacciaglia A,Vecchi M,Vitali LA,Varaldo PE,Giovanetti E

    更新日期:2007-04-01 00:00:00

  • In vitro activity and beta-lactamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin.

    abstract::Cefodizime, an iminomethoxy aminothiazolyl cephalosporin similar to moxalactam and ceftazidime, was less active (minimal inhibitory concentration, 1.6 to 12 micrograms) than cefazolin or cefotaxime against Staphylococcus aureus and Staphylococcus epidermidis. It inhibited Haemophilus and Neisseria spp. at less than 0....

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.23.6.907

    authors: Scully BE,Jules K,Neu HC

    更新日期:1983-06-01 00:00:00

  • Exploring ubiquinone biosynthesis inhibition as a strategy for improving atovaquone efficacy in malaria.

    abstract::Atovaquone (AV) acts on the malaria parasite by competing with ubiquinol (UQH2) for its union to the mitochondrial bc1 complex, preventing the ubiquinone-8,9 (UQ) redox recycling, which is a necessary step in pyrimidine biosynthesis. This study focused on UQ biosynthesis in Plasmodium falciparum and adopted proof-of-c...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01516-20

    authors: Verdaguer IB,Crispim M,Zafra CA,Sussmann RAC,Buriticá NL,Melo HR,Azevedo MF,Almeida FG,Kimura EA,Katzin AM

    更新日期:2021-01-25 00:00:00

  • Two 2-hydroxy-3-alkyl-1,4-naphthoquinones with in vitro and in vivo activities against Toxoplasma gondii.

    abstract::Two 3-alkyl-substituted 2-hydroxy-1,4-naphthoquinones, NSC 113452 (NSC52) and NSC 113455 (NSC55), were evaluated for activity against Toxoplasma gondii in vitro and in murine models of acute toxoplasmosis. In vitro, both NSC52 and NSC55 significantly inhibited intracellular replication of T. gondii. In vivo, each comp...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.9.2284

    authors: Khan AA,Nasr M,Araujo FG

    更新日期:1998-09-01 00:00:00

  • Effects of binding and bactericidal action of vancomycin on Bacillus licheniformis cell wall organization as probed by 15N nuclear magnetic resonance spectroscopy.

    abstract::The effects of binding and the bactericidal action of vancomycin on the arrangement and mobilities of cell wall polymers in Bacillus licheniformis were investigated by (15)N nuclear magnetic resonance spectroscopy. The bactericidal action of vancomycin led to reduced mobilities of cell wall teichoic acid and teichuron...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.14.5.695

    authors: Irving CS,Lapidot A

    更新日期:1978-11-01 00:00:00

  • In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice.

    abstract::Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against Pneumocystis and other microbes but are oftentimes toxic to the host. To identify potential anti-Pneumocystis agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modifi...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00126-06

    authors: Cushion MT,Walzer PD,Ashbaugh A,Rebholz S,Brubaker R,Vanden Eynde JJ,Mayence A,Huang TL

    更新日期:2006-07-01 00:00:00

  • Outcomes of moderate-to-severe Pneumocystis pneumonia treated with adjunctive steroid in non-HIV-infected patients.

    abstract::While it is well-known that adjunctive corticosteroid use improves the outcome of moderate-to-severe Pneumocystis jirovecii pneumonia (PcP) in patients with human immunodeficiency virus (HIV), there are limited data on its efficacy in non-HIV-infected patients with PcP. Patients undergoing fiber-optic bronchoscopy wit...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00669-11

    authors: Moon SM,Kim T,Sung H,Kim MN,Kim SH,Choi SH,Jeong JY,Woo JH,Kim YS,Lee SO

    更新日期:2011-10-01 00:00:00

  • Quinolone-induced upregulation of osteopontin gene promoter activity in human lung epithelial cell line A549.

    abstract::Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.06062-11

    authors: Shiratori B,Zhang J,Usami O,Chagan-Yasutan H,Suzuki Y,Nakajima C,Uede T,Hattori T

    更新日期:2012-06-01 00:00:00

  • [Combination of bacteriostatic and bactericidal drugs: lack of significant in vitro antagonism between penicillin, cephalothin, and rolitetracycline].

    abstract::Although it is generally believed that bactericidal and bacteriostatic drugs should not be combined in vivo, in vitro experiments using the checkerboard dilution technique revealed no antagonism between penicillin/cephalothin and rolitetracycline but rather additive or synergistic activity of either drug combination i...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.10.5.802

    authors: Daschner FD

    更新日期:1976-11-01 00:00:00

  • Effect of antiviral agents on replication of herpes simplex virus type 1 in brain cultures.

    abstract::An in vitro tissue culture system consisting of reaggregated embryonic brain cells was used to evaluate the inhibition of herpes simplex type 1 (HSV-1) by several antiviral compounds. The efficacy of acyclovir, vidarabine, bromovinyldeoxyuridine, and 9-(1,3-dihydroxy-2-propoxymethyl) guanine in HSV-1-infected Vero cel...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.30.6.840

    authors: Pulliam L,Panitch HS,Baringer JR,Dix RD

    更新日期:1986-12-01 00:00:00

  • Candida in the Respiratory Tract Potentially Triggers Galactomannan Positivity in Nonhematological Patients.

    abstract::BAL fluid samples from critically ill patients shared a rate of 29% false-positive galactomannan results. We aimed to determine whether Candida species abundance in BAL fluid causes galactomannan (GM) positivity. A total of 89 Candida culture-positive BAL fluid samples from patients without suspicion of invasive asper...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00138-19

    authors: Aigner M,Wanner M,Kreidl P,Lass-Flörl C,Lackner M

    更新日期:2019-05-24 00:00:00

  • In vitro and in vivo antibacterial activities of GV129606, a new broad-spectrum trinem.

    abstract::GV129606 is a new parenteral trinem antibiotic belonging to the beta-lactam class. It combines broad-spectrum activity (against gram-negative and -positive bacteria, aerobes and anaerobes), with high potency and resistance to beta-lactamases. Comparative in vitro and in vivo antibacterial activities were determined fo...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.41.12.2742

    authors: Di Modugno E,Broggio R,Erbetti I,Lowther J

    更新日期:1997-12-01 00:00:00

  • Photoinactivation of Venezuelan equine encephalitis virus mediated by tetracyclines.

    abstract::Demethylchlortetracycline and, to a lesser extent, chlortetracycline were found to mediate the in vitro photoinactivation of Venezuelan equine encephalitis virus. ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.10.1.176

    authors: Esparza J,Pina CI,Novo E

    更新日期:1976-07-01 00:00:00

  • Selection and characterization of human immunodeficiency virus type 1 variants resistant to the (+) and (-) enantiomers of 2'-deoxy-3'-oxa-4'-thio-5-fluorocytidine.

    abstract::Human immunodeficiency virus (HIV) type 1 (HIV-1) variants were selected for resistance to the (+) and (-) enantiomers of a novel nucleoside analogue, 2'-deoxy-3'-oxa-4'-thio-5-fluorocytidine (dOTFC), by use of the infectious molecular clone HIV HXB2D and the human T-cell line MT-4. The dOTFC-resistant variants that w...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.44.5.1127-1131.2000

    authors: Richard N,Salomon H,Rando R,Mansour T,Bowlin TL,Wainberg MA

    更新日期:2000-05-01 00:00:00

  • Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors.

    abstract::During its intraerythrocytic phase, the most lethal human malarial parasite, Plasmodium falciparum, digests host cell hemoglobin as a source of some of the amino acids required for its own protein synthesis. A number of parasite endopeptidases (including plasmepsins and falcipains) process the globin into small peptid...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01327-07

    authors: Cunningham E,Drag M,Kafarski P,Bell A

    更新日期:2008-09-01 00:00:00

  • In vitro and in vivo antibacterial activities of K-4619, a new semisynthetic aminoglycoside.

    abstract::The antibacterial activities of K-4619 (3-de-O-methylsporaricin A sulfate) were compared with those of sporaricin A, amikacin, dibekacin, and gentamicin. K-4619 exhibited a high order of activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against Providencia specie...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.26.2.187

    authors: Saino Y,Hattori Y,Koshi T,Kobayashi F,Oda T,Mitsuhashi S

    更新日期:1984-08-01 00:00:00

  • Diffusion of meropenem and imipenem through the outer membrane of Escherichia coli K-12 and correlation with their antibacterial activities.

    abstract::The outer membrane permeability to meropenem and imipenem in Escherichia coli K-12 was investigated, and its porin-deficient mutants were transformed with a constructed vector carrying the carbapenem-hydrolyzing CphA metallo-beta-lactamase gene. By using the method of Zimmermann and Rosselet, meropenem was shown to pe...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.36.9.1902

    authors: Cornaglia G,Guan L,Fontana R,Satta G

    更新日期:1992-09-01 00:00:00

  • Streptococcus pneumoniae isolates resistant to telithromycin.

    abstract::The telithromycin susceptibility of 210 erythromycin-resistant pneumococci was tested with the agar diffusion method. Twenty-six erm(B)-positive isolates showed heterogeneous resistance to telithromycin, which was manifested by the presence of colonies inside the inhibition zone. When these cells were cultured and tes...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.50.5.1855-1858.2006

    authors: Rantala M,Haanperä-Heikkinen M,Lindgren M,Seppälä H,Huovinen P,Jalava J

    更新日期:2006-05-01 00:00:00

  • Comparative toxicities of cephalosporin antibiotics in a rabbit kidney cell line (LLC-RK1).

    abstract::The rabbit kidney cell line LLC-RK1 was tested for its ability to discriminate the toxicities of six cephalosporin antibiotics according to their in vivo nephrotoxic potentials in rabbits. With the exception of cephalothin, which was markedly toxic to kidney cells in vitro, a good correlation between in vitro toxicity...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.32.3.314

    authors: Williams PD,Laska DA,Tay LK,Hottendorf GH

    更新日期:1988-03-01 00:00:00

  • Mutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux Mechanisms.

    abstract::Upregulated expression of efflux pumps, lpxC target mutations, LpxC protein overexpression, and mutations in fabG were previously shown to mediate single-step resistance to the LpxC inhibitor CHIR-090 in P. aeruginosa Single-step selection experiments using three recently described LpxC inhibitors (compounds 2, 3, and...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01490-19

    authors: Jones AK,Caughlan RE,Woods AL,Uehara K,Xie L,Barnes SW,Walker JR,Thompson KV,Ranjitkar S,Lee PS,Dean CR

    更新日期:2019-12-20 00:00:00

  • Antibiotic susceptibilities of Salmonella enterica serovar Typhi and S. enterica serovar Paratyphi A isolated from patients in Japan.

    abstract::The antibiotic susceptibilities of 62 strains of Salmonella enterica serovar Typhi and 37 strains of S. enterica serovar Paratyphi A were investigated with 18 antibiotics. Eighteen S. enterica serovar Typhi isolates and five S. enterica serovar Paratyphi A isolates were resistant to one or more antimicrobial agents, a...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.45.3.956-958.2001

    authors: Hirose K,Tamura K,Sagara H,Watanabe H

    更新日期:2001-03-01 00:00:00

  • Selection and characterization of beta-lactam-beta-lactamase inactivator-resistant mutants following PCR mutagenesis of the TEM-1 beta-lactamase gene.

    abstract::Mechanism-based inactivators of beta-lactamases are used to overcome the resistance of clinical pathogens to beta-lactam antibiotics. This strategy can itself be overcome by mutations of the beta-lactamase that compromise the effectiveness of their inactivation. We used PCR mutagenesis of the TEM-1 beta-lactamase gene...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.7.1542

    authors: Vakulenko SB,Geryk B,Kotra LP,Mobashery S,Lerner SA

    更新日期:1998-07-01 00:00:00

  • Antibiotic use before chlamydia and gonorrhea genital and extragenital screening in the sexually transmitted infection clinical setting.

    abstract::Background antibiotic use (i.e., administration of antibiotics not directly related to Chlamydia trachomatis or Neisseria gonorrhoeae infections) has been associated with a lower prevalence of genital C. trachomatis infection in a clinical setting. Associations with specific antibiotic types or with N. gonorrhoeae are...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.03932-14

    authors: Dukers-Muijrers NH,van Liere GA,Wolffs PF,Den Heijer C,Werner MI,Hoebe CJ

    更新日期:2015-01-01 00:00:00

  • CTX-M expression and selection of ertapenem resistance in Klebsiella pneumoniae and Escherichia coli.

    abstract::In vitro selection of mutants with decreased susceptibility to ertapenem was performed using Escherichia coli and Klebsiella pneumoniae clinical strains producing either the bla(CTX-M-2), bla(CTX-M-3), bla(CTX-M-9), or bla(CTX-M-15) gene. Frequencies of mutants with decreased susceptibilities to ertapenem were similar...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01007-08

    authors: Girlich D,Poirel L,Nordmann P

    更新日期:2009-02-01 00:00:00

  • Determination of robust ocular pharmacokinetic parameters in serum and vitreous humor of albino rabbits following systemic administration of ciprofloxacin from sparse data sets by using IT2S, a population pharmacokinetic modeling program.

    abstract::Robust determination of the concentration-time profile of anti-infective agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject. Vitreous humor and cerebrospinal fluid are obvious examples for which the determination of conce...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.39.8.1683

    authors: Drusano GL,Liu W,Perkins R,Madu A,Madu C,Mayers M,Miller MH

    更新日期:1995-08-01 00:00:00

  • Bloodstream infections with metallo-beta-lactamase-producing Pseudomonas aeruginosa: epidemiology, microbiology, and clinical outcomes.

    abstract::Pseudomonas aeruginosa strains that produce metallo-beta-lactamases (MBLs) are becoming increasingly prevalent. We evaluated the epidemiological and microbiological characteristics of monomicrobial bloodstream infections caused by MBL-producing P. aeruginosa isolates, as well as the clinical outcomes in patients with ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.50.1.388-390.2006

    authors: Marra AR,Pereira CA,Gales AC,Menezes LC,Cal RG,de Souza JM,Edmond MB,Faro C,Wey SB

    更新日期:2006-01-01 00:00:00

  • Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichia coli clinical isolates as a function of fluoroquinolone and multidrug resistance.

    abstract::In a single quantitative study, we measured acrA, acrB, tolC, mdfA, and norE expression in Escherichia coli clinical isolates by using real-time PCR. acrA and acrB overexpression strongly correlated with fluoroquinolone and multidrug resistance; tolC, mdfA, and norE expression did not. The order of abundance of efflux...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00996-10

    authors: Swick MC,Morgan-Linnell SK,Carlson KM,Zechiedrich L

    更新日期:2011-02-01 00:00:00

  • The macrolide roxithromycin impairs NADPH oxidase activation and alters translocation of its cytosolic components to the neutrophil membrane in vitro.

    abstract::We have studied the interference of roxithromycin with NADPH oxidase, the key enzymatic system for oxidant production by human neutrophils. Roxithromycin alters the reconstitution of an active enzyme and impairs the translocation to the outer membrane of the cytosolic components p47-phox and p67-phox. Interestingly, i...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.49.7.2986-2989.2005

    authors: Abdelghaffar H,Babin-Chevaye C,Labro MT

    更新日期:2005-07-01 00:00:00