Development and Validation of a Phenotypic High-Content Imaging Assay for Assessing the Antiviral Activity of Small-Molecule Inhibitors Targeting Zika Virus.

Abstract:

:Zika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat ZIKV infection, and accordingly, there is an unmet medical need for the discovery of new therapies. High-throughput drug screening efforts focusing on indirect readouts of cell viability are prone to a higher frequency of false positives in cases where the virus is viable in the cell but the cytopathic effect (CPE) is reduced or delayed. Here, we describe a fast and label-free phenotypic high-content imaging assay to detect cells affected by the virus-induced CPE using automated imaging and analysis. Protection from the CPE correlates with a decrease in viral antigen production, as observed by immunofluorescence. We trained our assay using a collection of nucleoside analogues with activity against ZIKV; the previously reported antiviral activities of 2'-C-methylribonucleosides and ribavirin against the Zika virus in Vero cells were confirmed using our developed method. To validate the ability of our assay to reveal new anti-ZIKV compounds, we profiled a novel library of 24 natural product derivatives and found compound 1 to be an inhibitor of the ZIKV-induced cytopathic effect; the activity of the compound was confirmed in human fetal neural stem cells (NSCs). The described technique can be easily leveraged as a primary screening assay for profiling of the activities of large compound libraries against ZIKV and can be expanded to other ZIKV strains and other cell lines displaying morphological changes upon ZIKV infection.

authors

Bernatchez JA,Yang Z,Coste M,Li J,Beck S,Liu Y,Clark AE,Zhu Z,Luna LA,Sohl CD,Purse BW,Li R,Siqueira-Neto JL

doi

10.1128/AAC.00725-18

subject

Has Abstract

pub_date

2018-09-24 00:00:00

issue

10

eissn

0066-4804

issn

1098-6596

pii

AAC.00725-18

journal_volume

62

pub_type

杂志文章
  • Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: a New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus.

    abstract::Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administrat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01776-19

    authors: Waterer G,Lord J,Hofmann T,Jouhikainen T

    更新日期:2020-02-21 00:00:00

  • Pharmacokinetics of cefamandole in patients with renal impairment.

    abstract::Cefamandole pharmacokinetics were investigated in 24 adult males with stable renal function and creatinine clearances of 0 to 139 ml/min. After intramuscular injection of 1.0 g of cefamandole, peak plasma concentrations were achieved between 1 and 2 h. Maximum plasma concentration and drug half-life increased as creat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.15.2.161

    authors: Czerwinski AW,Pederson JA

    更新日期:1979-02-01 00:00:00

  • Correlation of effects of erythromycin analogues on intact bacteria and on [14C]erythromycin binding to Escherichia coli ribosomes.

    abstract::The dissociation constants for binding to ribosomes from Escherichia coli and concentrations at which 50% inhibition of [(14)C]erythromycin binding to ribosomes occurred were determined for 45 erythromycin analogues. These values were correlated with their antibacterial activities against Bacillus subtilis. Compounds ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.6.4.489

    authors: Pestka S,Lemahieu R,Miller P

    更新日期:1974-10-01 00:00:00

  • Pseudomonas aeruginosa biofilm as a diffusion barrier to piperacillin.

    abstract::Pseudomonas aeruginosa 579 biofilms formed on dialysis membranes retarded piperacillin diffusion. Treatment of biofilms with 5.0 mM CaCl2.2H2O prevented diffusion. Biofilms permitted equilibration of [14C]glucose. Thin-layer chromatography of fluids distal to untreated (viable and nonviable) and viable Ca(2+)-treated ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.36.9.2054

    authors: Hoyle BD,Alcantara J,Costerton JW

    更新日期:1992-09-01 00:00:00

  • Treatment of anaerobic infections with metronidazole.

    abstract::The results of treatment of 10 patients with anaerobic infections with metronidazole are presented. Six patients were cured, three showed initial good response but circumstances required a change to another drug, and one patient did not respond. The unique spectrum of the drug, its pharmacology, and limitations are di...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/aac.7.5.672

    authors: Tally FP,Sutter VL,Finegold SM

    更新日期:1975-05-01 00:00:00

  • Development of a Multiplex Real-Time PCR Assay for Rapid Detection of Tigecycline Resistance Gene tet(X) Variants from Bacterial, Fecal, and Environmental Samples.

    abstract::We developed a multiplex real-time SYBR green-based PCR assay for rapid detection of tet(X) and its variants, including tet(X1) and tet(X2) and high-level tigecycline resistance genes tet(X3), tet(X4), and tet(X5). We showed that the real-time PCR assay developed had high linearity (R2 ≥ 0.996), sensitivity (low detec...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02292-19

    authors: Fu Y,Liu D,Song H,Liu Z,Jiang H,Wang Y

    更新日期:2020-03-24 00:00:00

  • In vivo evaluation of tigemonam, a novel oral monobactam.

    abstract::Tigemonam, a new monobactam with excellent activity against gram-negative bacteria, was evaluated for in vivo efficacy and absorption after oral administration to laboratory animals. Tigemonam is absorbed when administered orally to mice and dogs. In a variety of gram-negative systemic infections in mice, orally admin...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.31.2.226

    authors: Clark JM,Olsen SJ,Weinberg DS,Dalvi M,Whitney RR,Bonner DP,Sykes RB

    更新日期:1987-02-01 00:00:00

  • Quality assessment of U.S. marketplace vancomycin for injection products using high-resolution liquid chromatography-mass spectrometry and potency assays.

    abstract::In response to a published concern about the potency and quality of generic vancomycin products, the United States Food and Drug Administration investigated a small sampling of the vancomycin products available in North America with regard to purity, content, and potency. To facilitate identification of impurities, a ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00164-12

    authors: Hadwiger ME,Sommers CD,Mans DJ,Patel V,Boyne MT 2nd

    更新日期:2012-06-01 00:00:00

  • Safety, tolerability, and pharmacokinetics of intravenous nemonoxacin in healthy chinese volunteers.

    abstract::Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, p...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章,随机对照试验

    doi:10.1128/AAC.02972-14

    authors: Cao GY,Zhang J,Zhang YY,Guo BN,Yu JC,Wu XJ,Chen YC,Wu JF,Shi YG

    更新日期:2014-10-01 00:00:00

  • Unusual Escherichia coli PBP 3 Insertion Sequence Identified from a Collection of Carbapenem-Resistant Enterobacteriaceae Tested In Vitro with a Combination of Ceftazidime-, Ceftaroline-, or Aztreonam-Avibactam.

    abstract::Carbapenemase-producing Enterobacteriaceae isolates (n = 110) from health care centers in central Indiana (from 2010 to 2013) were tested for susceptibility to combinations of avibactam (4 μg/ml) with ceftazidime, ceftaroline, or aztreonam. MIC50/MIC90 values were 1/2 μg/ml (ceftazidime-avibactam), 0.5/2 μg/ml (ceftar...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00389-17

    authors: Zhang Y,Kashikar A,Brown CA,Denys G,Bush K

    更新日期:2017-07-25 00:00:00

  • Molecular Analysis of a blaIMP-1-Harboring Class 3 Integron in Multidrug-Resistant Pseudomonas fulva.

    abstract::A multidrug-resistant (MDR) Pseudomonas fulva strain was isolated in 2006 from a urine sample. The isolate harbored the blaIMP-1 gene, which was located in a chromosomal Tn402-like class 3 integron as a gene cassette array of aacA31-fosE-blaIMP-1 Two mutations in gyrA and one mutation in parC were detected in quinolon...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00701-18

    authors: Yamamoto M,Matsumura Y,Gomi R,Matsuda T,Nakano S,Nagao M,Tanaka M,Ichiyama S

    更新日期:2018-07-27 00:00:00

  • Clinical and bacteriological evaluation of netilmicin in gram-negative infections.

    abstract::A preliminary study was conducted with netilmicin, a new aminoglycoside antibiotic. Its effectiveness was evaluated in vitro against 546 strains of Enterobacteriaceae and Pseudomonas aeruginosa isolated from clinical material. Its effectiveness against gentamicin-susceptible strains was roughly similar to that of gent...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/aac.12.4.503

    authors: Klastersky J,Meunier-Carpentier F,Coppens-Kahan L,Daneau D,Prevost JM

    更新日期:1977-10-01 00:00:00

  • Novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein: enzymatic analysis of the mutant proteins.

    abstract::Using the techniques of gap misrepair mutagenesis and site-directed mutagenesis, we have generated two novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein. DNA sequencing showed these mutations to be Ser-83----Ala and Gln-106----Arg. The mutant proteins were overproduced and purified, and...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.35.2.335

    authors: Hallett P,Maxwell A

    更新日期:1991-02-01 00:00:00

  • Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects.

    abstract::Vaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, do...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章,随机对照试验

    doi:10.1128/AAC.00568-16

    authors: Griffith DC,Loutit JS,Morgan EE,Durso S,Dudley MN

    更新日期:2016-09-23 00:00:00

  • Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam.

    abstract::In 2016, we identified a new class A carbapenemase, VCC-1, in a nontoxigenic Vibrio cholerae strain that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1-producing V. cholerae isolates were recovered along the German coastline. These isolates a...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02112-18

    authors: Mangat CS,Vadlamani G,Holicek V,Chu M,Larmour VLC,Vocadlo DJ,Mulvey MR,Mark BL

    更新日期:2019-03-27 00:00:00

  • Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses.

    abstract::The activities of the purine acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) against two human and five animal strains of cytomegalovirus were compared with those of acyclovir. DHPG was significantly more active than acyclovir against all but one (mouse cytomegalovirus) of the strains tested, with 5...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.28.2.240

    authors: Freitas VR,Smee DF,Chernow M,Boehme R,Matthews TR

    更新日期:1985-08-01 00:00:00

  • Activity of compound G2 isolated from alfalfa roots in experimental dermatophyte infection.

    abstract::Compound G2 isolated from alfalfa roots was applied topically to skin lesions of guinea pigs experimentally infected with the dermatophyte Trichophyton mentagrophytes var. granulare. After 12 to 15 applications, 80% of the infected lesions were cured, as judged by clinical and microbial criteria, compared with 20% of ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.34.8.1600

    authors: Evron R,Guizie M,Zehavi U,Polacheck I

    更新日期:1990-08-01 00:00:00

  • Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

    abstract::We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% ef...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01540-10

    authors: Ide K,Aoki M,Amano M,Koh Y,Yedidi RS,Das D,Leschenko S,Chapsal B,Ghosh AK,Mitsuya H

    更新日期:2011-04-01 00:00:00

  • Activities of isoniazid alone and in combination with other drugs against Mycobacterium avium infection in beige mice.

    abstract::Monotherapy with isoniazid or amikacin or clarithromycin or combinations of two of these drugs showed nil to modest therapeutic activity in beige mice infected with Mycobacterium avium. However, the combination of all three, isoniazid-amikacin-clarithromycin, markedly reduced CFUs in both spleens and lungs after 91 da...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.3.712

    authors: Fattorini L,Xiao Y,Mattei M,Li Y,Iona E,Ricci ML,Thoresen OF,Creti R,Orefici G

    更新日期:1998-03-01 00:00:00

  • Influence of reduced susceptibility to glycopeptides on activities of vancomycin and teicoplanin against Staphylococcus aureus in experimental endocarditis.

    abstract::The influence of reduced susceptibilities to glycopeptides on the activities of vancomycin and teicoplanin against an isogenic pair of clinical Staphylococcus aureus strains in experimental endocarditis was investigated. While vancomycin was similarly active against both strains, teicoplanin was approximately 100-fold...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.47.6.2018-2021.2003

    authors: Pavie J,Lefort A,Ploy MC,Massias L,Chau F,Garry L,Denis F,Fantin B

    更新日期:2003-06-01 00:00:00

  • Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity.

    abstract::The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the vir...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.05292-11

    authors: Johnson BC,Métifiot M,Pommier Y,Hughes SH

    更新日期:2012-01-01 00:00:00

  • Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin.

    abstract::The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents C...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.38.4.742

    authors: Couture M,Simard M,Gourde P,Lessard C,Gurnani K,Lin L,Carrier D,Bergeron MG,Beauchamp D

    更新日期:1994-04-01 00:00:00

  • Glutathione-Disrupted Biofilms of Clinical Pseudomonas aeruginosa Strains Exhibit an Enhanced Antibiotic Effect and a Novel Biofilm Transcriptome.

    abstract::Pseudomonas aeruginosa infections result in high morbidity and mortality rates for individuals with cystic fibrosis (CF), with premature death often occurring. These infections are complicated by the formation of biofilms in the sputum. Antibiotic therapy is stymied by antibiotic resistance of the biofilm matrix, maki...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02919-15

    authors: Klare W,Das T,Ibugo A,Buckle E,Manefield M,Manos J

    更新日期:2016-07-22 00:00:00

  • Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations.

    abstract::The genetic basis for fluoroquinolone resistance was examined in 30 high-level fluoroquinolone-resistant Escherichia coli clinical isolates from Beijing, China. Each strain also demonstrated resistance to a variety of other antibiotics. PCR sequence analysis of the quinolone resistance-determining region of the topois...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.45.5.1515-1521.2001

    authors: Wang H,Dzink-Fox JL,Chen M,Levy SB

    更新日期:2001-05-01 00:00:00

  • Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone.

    abstract::Enterovirus 71 is one of the most important pathogens in the family of Picornaviridae that can cause severe complications in the postpoliovirus era, such as encephalitis, pulmonary edema, and even death. Pyridyl imidazolidinone is a novel class of potent and selective human enterovirus 71 inhibitor. Pyridyl imidazolid...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.48.9.3523-3529.2004

    authors: Shih SR,Tsai MC,Tseng SN,Won KF,Shia KS,Li WT,Chern JH,Chen GW,Lee CC,Lee YC,Peng KC,Chao YS

    更新日期:2004-09-01 00:00:00

  • Effects of a high-fat meal on the relative oral bioavailability of piperaquine.

    abstract::Piperaquine (PQ) is an antimalarial drug whose high lipid solubility suggests that its absorption can be increased by a high-fat meal. We examined the pharmacokinetics of PQ phosphate (500 mg given orally) in the fasting state and after a high-fat meal in eight healthy Caucasian volunteers (randomized crossover). Plas...

    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.49.6.2407-2411.2005

    authors: Sim IK,Davis TM,Ilett KF

    更新日期:2005-06-01 00:00:00

  • New transposon Tn6133 in methicillin-resistant Staphylococcus aureus ST398 contains vga(E), a novel streptogramin A, pleuromutilin, and lincosamide resistance gene.

    abstract::A novel streptogramin A, pleuromutilin, and lincosamide resistance determinant, Vga(E), was identified in porcine methicillin-resistant Staphylococcus aureus (MRSA) ST398. The vga(E) gene encoded a 524-amino-acid protein belonging to the ABC transporter family. It was found on a multidrug resistance-conferring transpo...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00528-11

    authors: Schwendener S,Perreten V

    更新日期:2011-10-01 00:00:00

  • A novel gene cassette, aacA43, in a plasmid-borne class 1 integron.

    abstract::A novel gene cassette, aacA43, was identified in the aadB-aacA43-oxa10-smr2 cassette array in a class 1 integron. Like related aminoglycoside-(6')-acetyltransferases, AacA43 confers clinically relevant resistance to kanamycin, tobramycin, and some less-used aminoglycosides but not to gentamicin. Although transferable ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01582-10

    authors: Partridge SR,Thomas LC,Ginn AN,Wiklendt AM,Kyme P,Iredell JR

    更新日期:2011-06-01 00:00:00

  • Characterization of penicillin-binding protein 2 of Staphylococcus aureus: deacylation reaction and identification of two penicillin-binding peptides.

    abstract::Penicillin-binding protein (PBP) 2 is the major PBP of five that have been identified in susceptible strains of Staphylococcus aureus. Beta-lactam antibiotic binding to PBP 2 is important for the antibacterial effect. Antibiotic binding to PBP 2 in strain 209P was examined with sodium dodecyl sulfate-polyacrylamide ge...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.36.3.656

    authors: Chambers HF,Miick C

    更新日期:1992-03-01 00:00:00

  • In Vivo Characterization of the Activation and Interaction of the VanR-VanS Two-Component Regulatory System Controlling Glycopeptide Antibiotic Resistance in Two Related Streptomyces Species.

    abstract::The VanR-VanS two-component system is responsible for inducing resistance to glycopeptide antibiotics in various bacteria. We have performed a comparative study of the VanR-VanS systems from two streptomyces strains, Streptomyces coelicolor and Streptomyces toyocaensis, to characterize how the two proteins cooperate t...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01367-15

    authors: Novotna GB,Kwun MJ,Hong HJ

    更新日期:2015-12-28 00:00:00