Abstract:
:VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Byrn RA,Jones SM,Bennett HB,Bral C,Clark MP,Jacobs MD,Kwong AD,Ledeboer MW,Leeman JR,McNeil CF,Murcko MA,Nezami A,Perola E,Rijnbrand R,Saxena K,Tsai AW,Zhou Y,Charifson PSdoi
10.1128/AAC.04623-14subject
Has Abstractpub_date
2015-03-01 00:00:00pages
1569-82issue
3eissn
0066-4804issn
1098-6596pii
AAC.04623-14journal_volume
59pub_type
杂志文章abstract::There are currently few or no published data on the amount of cerebrospinal fluid (CSF) penetration of daptomycin in patients with suspected or documented neurosurgical infections. We conducted a prospective study, assessing the pharmacokinetics and CSF penetration of a single intravenous daptomycin dose administered ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01741-10
更新日期:2011-07-01 00:00:00
abstract::Replication of hepatitis C virus (HCV) RNA is catalyzed by the virally encoded RNA-dependent RNA polymerase NS5B. It is believed that the viral polymerase utilizes a de novo or primer-independent mechanism for initiation of RNA synthesis. Our previous work has shown that dinucleotides were efficient initiation molecul...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.8.2674-2681.2003
更新日期:2003-08-01 00:00:00
abstract::Cryomicrotomy has been used as a new technique for removing gastric mucosae from adult guinea pigs for the study of amoxicillin secretion across gastric mucosae. This method allowed a very regular thickness of the removed surface layer of mucosa to be obtained with good reproducibility. Gastric superficial mucosa conc...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.3.766
更新日期:1995-03-01 00:00:00
abstract::The CcrA beta-lactamase from Bacteroides fragilis TAL3636 was cloned into Escherichia coli and purified from inclusion bodies. This group 3 metalloenzyme hydrolyzed most beta-lactam antibiotics, including cephamycins and carbapenems. Following inhibition by chelators, enzyme activity was recovered with the cations Zn2...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.5.1155
更新日期:1992-05-01 00:00:00
abstract::The pharmacokinetics and bacteriological effect of ceftazidime were evaluated in rabbits experimentally infected with Streptococcus pneumoniae, Haemophilus influenzae type b, and Escherichia coli K1. The mean penetration of ceftazidime into cerebrospinal fluid after single-dose or constant-infusion administration rang...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.23.2.213
更新日期:1983-02-01 00:00:00
abstract::Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.01540-09
更新日期:2010-06-01 00:00:00
abstract::Clinical treatment failures have been reported to occur in early Lyme borreliosis (LB) for many suitable antimicrobial agents. Investigations of possible resistance mechanisms of the Borrelia burgdorferi complex must analyze clinical isolates obtained from LB patients, despite their receiving antibiotic treatment. Her...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.49.4.1294-1301.2005
更新日期:2005-04-01 00:00:00
abstract::Retrocyclins are humanized versions of the -defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00267-11
更新日期:2011-09-01 00:00:00
abstract::Clinical isolates of Klebsiella pneumoniae resistant to carbapenems are being isolated with increasing frequency. Loss of the expression of the major nonspecific porins OmpK35/36 is a frequent feature in these isolates. In this study, we looked for porins that could compensate for the loss of the major porins in carba...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00309-11
更新日期:2011-10-01 00:00:00
abstract::Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.3.1169-1176.2005
更新日期:2005-03-01 00:00:00
abstract::The accumulation of quinolones by Escherichia coli JF568, Pseudomonas aeruginosa PAO1, and Staphylococcus aureus ATCC 29213 was measured by a modified fluorometric assay (J. S. Chapman and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:27-29, 1989). The quinolones examined were fleroxacin, pefloxacin, norflox...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.8.1601
更新日期:1992-08-01 00:00:00
abstract::This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoa...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.02036-13
更新日期:2014-01-01 00:00:00
abstract::Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae, new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed. In this study, we identified a p...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02043-18
更新日期:2019-03-27 00:00:00
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
doi:10.1128/aac.44.10.2915-2918.2000
更新日期:2000-10-01 00:00:00
abstract::Although the use of probiotics based on Bacillus strains to fight off intestinal pathogens and antibiotic-associated diarrhea is widespread, the mechanisms involved in producing their beneficial effects remain unclear. Here, we studied the ability of compounds secreted by the probiotic Bacillus clausii strain O/C to c...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02815-15
更新日期:2016-05-23 00:00:00
abstract::The objective of the present study was to test the hypothesis that treatment of schistosomiasis mansoni with praziquantel can alter significantly the immune response of patients and generate a reversal of the level of fibrosis. Peripheral blood mononuclear cell (PBMC) samples were collected from, and abdominal ultraso...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.00173-08
更新日期:2008-08-01 00:00:00
abstract::(S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP], cyclic (S)-HPMPA [(S)-cHPMPA], 9-(2-phosphonylmethoxyethoxyethyl)-2,6-diaminopurine (PMEDAP), and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] were examined fo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.11.2440
更新日期:1991-11-01 00:00:00
abstract::Polymyxin B (PMB) binds to and neutralizes endotoxin, but its systemic clinical utility is limited by neuro- and nephrotoxicity. PMX622 is a covalent conjugate of PMB and Dextran-70 designed to retain the ability of PMB to neutralize endotoxin and to retain the favorable colloidal, pharmacokinetic, and metabolic prope...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.48.8.2987-2992.2004
更新日期:2004-08-01 00:00:00
abstract::A rapid (6-7 hr), modified Kirby-Bauer disk-susceptibility method, by which derivatives of tetrazolium dyes are used to enhance delineation between areas of growth and zones of inhibition, has been developed. Inoculated petri plates, prepared by the Kirby-Bauer method, were sprayed, after 6 to 7 hr of incubation (37 C...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.3.3.418
更新日期:1973-03-01 00:00:00
abstract::Kingella kingae is the major pathogen causing osteoarticular infections (OAI) in young children in numerous countries. Plasmid-borne TEM-1 penicillinase production has been sporadically detected in a few countries but not in continental Europe, despite a high prevalence of K. kingae infections. We describe here for th...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03562-14
更新日期:2014-10-01 00:00:00
abstract::A total of 100 and 97% of Haemophilus influenzae type b strains from major infections were susceptible, respectively, to levels of rifampin and sulfisoxazole attainable in saliva. It is theoretically feasible to eliminate Haemophilus influenzae from the nasopharynx with these drugs. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.6.969
更新日期:1978-06-01 00:00:00
abstract::The ultrastructural alterations induced in vitro by ICI 195,739, a recently developed bis-triazole derivative with potent antiproliferative effects on Trypanosoma (Schizotrypanum) cruzi, are reported. On epimastigotes, the triazole at its minimum growth-inhibitory concentration (0.1 microM) produced immediately (withi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.4.736
更新日期:1991-04-01 00:00:00
abstract::Ceftizoxime was evaluated in the treatment of 18 patients (6 adults and 12 children) with bacterial meningitis. In seven patients Haemophilus influenzae was the causative agent, in three Neisseria meningitidis, in five Streptococcus pneumoniae, and in one each alpha-streptococcus and Escherichia coli; one case was cul...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.2.258
更新日期:1984-02-01 00:00:00
abstract::The iron-chelating drug deferoxamine (DFO) has been shown to be active in animal models of Pneumocystis carinii pneumonia (PCP), with effective daily intraperitoneal bolus dosages being 400 and 1,000 mg of DFO mesylate kg of body weight-1 in mouse and rat models, respectively. Continuous infusion produced a moderately...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.9.2023
更新日期:1995-09-01 00:00:00
abstract::3-O-(3',3'-Dimethylsuccinyl) betulinic acid (DSB), also known as PA-457, bevirimat (BVM), or MPC-4326, is a novel HIV-1 maturation inhibitor. Unlike protease inhibitors, BVM blocks the cleavage of the Gag capsid precursor (CA-SP1) to mature capsid (CA) protein, resulting in the release of immature, noninfectious viral...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01435-10
更新日期:2011-07-01 00:00:00
abstract::Acyclovir [9-(2-hydroxyethoxymethyl)guanine] (ACV), a potent antiviral compound, was phosphorylated to the same extent by extracts from untreated and iododeoxyuridine-treated Epstein-Barr virus-containing latent D98/HR-1 somatic hybrid cells. ATP was the preferred phosphate donor over other nucleoside triphosphates. T...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.24.1.10
更新日期:1983-07-01 00:00:00
abstract::Nephrotoxicity was more marked in rats receiving isepamicin at midlight than at middark. And, the once-daily administration at middark induced a lesser degree of nephrotoxicity than the twice-daily injection, which indicates that the once-daily treatment therapy may have potential value in the clinical use of aminogly...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.9.2042
更新日期:1993-09-01 00:00:00
abstract::Resistance of influenza viruses to antiviral drugs can emerge following medication or may result from natural variation. Two classes of anti-influenza virus drugs targeting either the M2 protein (amantadine and rimantadine) or neuraminidase (NA; oseltamivir and zanamivir) are currently licensed. These drugs are expect...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01446-08
更新日期:2009-03-01 00:00:00
abstract::The role of Ser-235 in the catalytic mechanism of the TEM-1 beta-lactamase has been explored by the study of a mutant enzyme in which Ser-235 has been substituted by alanine (Ala-235 mutant enzyme). A comparative kinetic analysis of both the wild-type and the Ala-235 TEM-1 enzymes revealed little effect of this substi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.11.2438
更新日期:1993-11-01 00:00:00
abstract::The efficacy of a new class of drugs for Pneumocystis carinii pneumonitis was demonstrated. 566C80, a hydroxynaphthoquinone, administered orally in a dose of greater than or equal to 100 mg/kg of body weight per day prophylactically prevented P. carinii pneumonitis in 90% or more of rats, while all untreated control a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.2.225
更新日期:1990-02-01 00:00:00