Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box.

Abstract:

:Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti-Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC50) were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC50 of less than 2 μM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC50 of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii, with IC50s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis.

authors

Spalenka J,Escotte-Binet S,Bakiri A,Hubert J,Renault JH,Velard F,Duchateau S,Aubert D,Huguenin A,Villena I

doi

10.1128/AAC.01640-17

subject

Has Abstract

pub_date

2018-01-25 00:00:00

issue

2

eissn

0066-4804

issn

1098-6596

pii

AAC.01640-17

journal_volume

62

pub_type

杂志文章
  • In vitro activity of a new antibiotic, NVP-PDF386 (VRC4887), against Chlamydia pneumoniae.

    abstract::The in vitro activity of NVP-PDF386 (VRC4887), a novel new peptide deformylase inhibitor, and those of levofloxacin and clarithromycin were tested against 21 isolates of Chlamydia pneumoniae. The MIC at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates wer...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.47.4.1447-1448.2003

    authors: Roblin PM,Hammerschlag MR

    更新日期:2003-04-01 00:00:00

  • Age-related effects on nelfinavir and M8 pharmacokinetics: a population study with 182 children.

    abstract::As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concent...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.50.3.910-916.2006

    authors: Hirt D,Urien S,Jullien V,Firtion G,Rey E,Pons G,Blanche S,Treluyer JM

    更新日期:2006-03-01 00:00:00

  • Determination of pyrazinamide MICs for Mycobacterium tuberculosis at different pHs by the radiometric method.

    abstract::The MICs of pyrazinamide (PZA) were determined for Mycobacterium tuberculosis cultivated under different pH conditions in 7H12 liquid medium. Mycobacterial growth was monitored by the radiometric method (BACTEC system; Johnston Laboratories, Inc., Towson, Md.). We observed a predictable eightfold difference between th...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.32.7.1002

    authors: Salfinger M,Heifets LB

    更新日期:1988-07-01 00:00:00

  • Characterization of imidazo[4,5-d]pyridazine nucleosides as modulators of unwinding reaction mediated by West Nile virus nucleoside triphosphatase/helicase: evidence for activity on the level of substrate and/or enzyme.

    abstract::Compounds that interact with DNA or RNA generally act as inhibitors of enzymes that unwind DNA or RNA. In the present study we describe the synthesis and properties of some nucleoside analogues that interact with double-stranded DNA but that, in contrast, facilitate the unwinding reaction mediated by West Nile (WN) vi...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.46.5.1231-1239.2002

    authors: Borowski P,Lang M,Haag A,Schmitz H,Choe J,Chen HM,Hosmane RS

    更新日期:2002-05-01 00:00:00

  • Genome-wide expression patterns in Saccharomyces cerevisiae: comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol.

    abstract::Enzymes in the ergosterol-biosynthetic pathway are the targets of a number of antifungal agents including azoles, allylamines, and morpholines. In order to understand the response of Saccharomyces cerevisiae to perturbations in the ergosterol pathway, genome-wide transcript profiles following exposure to a number of a...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.44.5.1255-1265.2000

    authors: Bammert GF,Fostel JM

    更新日期:2000-05-01 00:00:00

  • Prolonged Exposure to β-Lactam Antibiotics Reestablishes Susceptibility of Daptomycin-Nonsusceptible Staphylococcus aureus to Daptomycin.

    abstract::Daptomycin-nonsusceptible (DAP-NS) Staphylococcus aureus often exhibits gain-in-function mutations in the mprF gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against methicillin-resistant S. aureus (MRSA), may prevent the emergence of mprF mutations and DAP-NS....

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00890-20

    authors: Jenson RE,Baines SL,Howden BP,Mishra NN,Farah S,Lew C,Berti AD,Shukla SK,Bayer AS,Rose WE

    更新日期:2020-08-20 00:00:00

  • Standardization of disk diffusion test and its clinical significance for susceptibility testing of metronidazole against Helicobacter pylori.

    abstract::Susceptibilities of 121 clinical Helicobacter pylori strains to metronidazole were determined by both a 5-micrograms metronidazole disk diffusion test and a plate dilution method in duplicate and after different periods of incubation. The distribution of MICs of metronidazole against H. pylori among the strains was fo...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/aac.38.10.2357

    authors: Xia H,Keane CT,Beattie S,O'Morain CA

    更新日期:1994-10-01 00:00:00

  • Role of Fks1p and matrix glucan in Candida albicans biofilm resistance to an echinocandin, pyrimidine, and polyene.

    abstract::Candida infections frequently involve drug-resistant biofilm growth on device surfaces. Glucan synthase gene FKS1 has been linked to triazole resistance in Candida biofilms. We tested the impact of FKS1 modulation on susceptibility to additional antifungal classes. Reduction of FKS1 expression rendered biofilms more s...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00227-10

    authors: Nett JE,Crawford K,Marchillo K,Andes DR

    更新日期:2010-08-01 00:00:00

  • Colicinogeny of Escherichia coli MRE 600.

    abstract::Escherichia coli MRE 600 is a colicinogenic bacterium. Its colicinogenic activity may be ascribed mostly to colicin E1, although it produces a small amount of another, as yet unidentified, colicin. ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.14.5.797

    authors: Salaj-Smic E

    更新日期:1978-11-01 00:00:00

  • Susceptibility of clinical isolates of bacteria to cefoxitin and cephalothin.

    abstract::The susceptibility of 4,929 unselected clinical isolates of bacteria to cefoxitin and cephalothin was determined by the single-disk method, using a computer-associated electronic zone analyzer to obtain, record, and process measurements of sizes of zones of inhibition. Both cefoxitin and cephalothin were effective aga...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.6.3.320

    authors: Moellering RC Jr,Dray M,Kunz LJ

    更新日期:1974-09-01 00:00:00

  • Iron requirement in the bactericidal mechanism of streptonigrin.

    abstract::Mutants of Escherichia coli K-12 that are unable to make use of the enterochelin transport system were used to confirm that streptonigrin requires iron for its bactericidal action. Correlation of viability studies and 55Fe3+ uptake experiments showed that killing by streptonigrin increased with an increase in 55Fe3+ u...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.22.6.961

    authors: Yeowell HN,White JR

    更新日期:1982-12-01 00:00:00

  • Effect of pyrimido[1,6-a]benzimidazoles, quinolones, and Ca2+ on the DNA gyrase-mediated cleavage reaction.

    abstract::The quinolones inhibit the A subunit of DNA gyrase in the presence of Mg2+ by interrupting the DNA breakage and resealing steps, and the latter step is also retarded without quinolones if Mg2+ is replaced by Ca2+. Pyrimido[1,6-a]benzimidazoles have been found to represent a new class of potent DNA gyrase inhibitors wh...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.39.1.163

    authors: Gmünder H,Kuratli K,Keck W

    更新日期:1995-01-01 00:00:00

  • Herpesvirus hominis infection in newborn mice: treatment with interferon inducer polyinosinic-polycytidylic acid.

    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

    authors: Kern ER,Overall JC Jr,Glasgow LA

    更新日期:1975-06-01 00:00:00

  • Analysis of pH and buffer effects on flucytosine activity in broth dilution susceptibility testing of Candida albicans in two synthetic media.

    abstract::We examined the influences of different pH levels and three different buffers on flucytosine activity against 12 isolates of Candida albicans in two synthetic media, yeast nitrogen base (YNB) and synthetic amino acid medium-fungal (SAAMF), using broth dilution techniques and measuring the endpoints of visual MICs and ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.26.3.364

    authors: Calhoun DL,Galgiani JN

    更新日期:1984-09-01 00:00:00

  • Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients.

    abstract::The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m(2) polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (me...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/AAC.45.11.3148-3155.2001

    authors: Malone RS,Fish DN,Abraham E,Teitelbaum I

    更新日期:2001-11-01 00:00:00

  • Novel Carbapenemases FLC-1 and IMI-2 Encoded by an Enterobacter cloacae Complex Isolated from Food Products.

    abstract::Food for human consumption is screened widely for the presence of antibiotic-resistant bacteria to assess the potential for transfer of resistant bacteria to the general population. Here, we describe an Enterobacter cloacae complex isolated from imported seafood that encodes two carbapenemases on two distinct plasmids...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02338-18

    authors: Brouwer MSM,Tehrani KHME,Rapallini M,Geurts Y,Kant A,Harders F,Mashayekhi V,Martin NI,Bossers A,Mevius DJ,Wit B,Veldman KT

    更新日期:2019-05-24 00:00:00

  • Placental transfer of darunavir in an ex vivo human cotyledon perfusion model.

    abstract::Placental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (± the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0%±...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.03184-14

    authors: Mandelbrot L,Duro D,Belissa E,Peytavin G

    更新日期:2014-09-01 00:00:00

  • Contributions of yap1 Mutation and Subsequent atrF Upregulation to Voriconazole Resistance in Aspergillus flavus.

    abstract::Aspergillus flavus is the second most significant pathogenic cause of invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure of A. flavus to subinhibitory concentrations of VRC in vitro cau...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01216-18

    authors: Ukai Y,Kuroiwa M,Kurihara N,Naruse H,Homma T,Maki H,Naito A

    更新日期:2018-10-24 00:00:00

  • HIV-positive nigerian adults harbor significantly higher serum lumefantrine levels than HIV-negative individuals seven days after treatment for Plasmodium falciparum infection.

    abstract::Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumef...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02508-12

    authors: Chijioke-Nwauche I,van Wyk A,Nwauche C,Beshir KB,Kaur H,Sutherland CJ

    更新日期:2013-09-01 00:00:00

  • Distribution of extended-spectrum beta-lactamases in clinical isolates of Enterobacteriaceae in Vietnam.

    abstract::Among 730 Escherichia coli, 438 Klebsiella pneumoniae, and 141 Proteus mirabilis isolates obtained between September 2000 and September 2001 in seven hospitals in Ho Chi Minh City, Vietnam, 26.6% were resistant to ceftazidime, 30% were resistant to cefotaxime, 31.5% were resistant to ceftriaxone, 15.9% were resistant ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.46.12.3739-3743.2002

    authors: Cao V,Lambert T,Nhu DQ,Loan HK,Hoang NK,Arlet G,Courvalin P

    更新日期:2002-12-01 00:00:00

  • Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study.

    abstract::Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits ba...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02760-16

    authors: Nayak SU,Griffiss JM,Blumer J,O'Riordan MA,Gray W,McKenzie R,Jurao RA,An AT,Le M,Bell SJ,Ochsner UA,Jarvis TC,Janjic N,Zenilman JM

    更新日期:2017-07-25 00:00:00

  • Comparison of the effects of 3'-azidothymidine with those of neutralizing antibodies on simian immunodeficiency virus infection in macrophages.

    abstract::We previously showed that simian immunodeficiency virus-infected macaque macrophages contacting uninfected CD4+ lymphocytes caused extensive cell fusion and synthesis of phlogistic cytokines. In this study, macaque macrophage cultures inoculated with SIVmac251 and treated simultaneously with 10 microM 3'-azidothymidin...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.37.2.360

    authors: McEntee MF,Flexner C,Farzadegan H,Pitha P,Narayan O

    更新日期:1993-02-01 00:00:00

  • Emergence of gentamicin- and carbenicillin-resistant Pseudomonas aeruginosa in a hospital environment.

    abstract::Strains of Pseudomonas aeruginosa resistant to either gentamicin or carbenicillin have been noted since their introduction into clinical use. During a 6-month period, twice-weekly cultures were obtained from all patients treated with either gentamicin or carbenicillin and from all patients with a positive culture for ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.9.3.474

    authors: Gaman W,Cates C,Snelling CF,Lank B,Ronald AR

    更新日期:1976-03-01 00:00:00

  • Inhibition of aminoglycoside 6'-N-acetyltransferase type Ib-mediated amikacin resistance in Klebsiella pneumoniae by zinc and copper pyrithione.

    abstract::The in vitro activity of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] was inhibited by CuCl2 with a 50% inhibitory concentration (IC50) of 2.8 μM. The growth of an amikacin-resistant Klebsiella pneumoniae strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by t...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01106-15

    authors: Chiem K,Fuentes BA,Lin DL,Tran T,Jackson A,Ramirez MS,Tolmasky ME

    更新日期:2015-09-01 00:00:00

  • Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility.

    abstract::Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00261-20

    authors: Liston SD,Whitesell L,Kapoor M,Shaw KJ,Cowen LE

    更新日期:2020-04-21 00:00:00

  • Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment.

    abstract::The effects of renal impairment on the pharmacokinetics of ceftriaxone in humans were examined after intravenous infusion of a 1-g dose over 15 min to 30 renally impaired patients. The study included 12 dialysis patients and 18 patients with severe, moderate, or mild renal impairment. Plasma and, where appropriate, ur...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.25.4.438

    authors: Patel IH,Sugihara JG,Weinfeld RE,Wong EG,Siemsen AW,Berman SJ

    更新日期:1984-04-01 00:00:00

  • Inhibition of gene expression and growth by antisense peptide nucleic acids in a multiresistant beta-lactamase-producing Klebsiella pneumoniae strain.

    abstract::Klebsiella pneumoniae causes common and severe hospital- and community-acquired infections with a high incidence of multidrug resistance. The emergence and spread of beta-lactamase-producing K. pneumoniae strains highlight the need to develop new therapeutic strategies. In this study, we developed antisense peptide nu...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00709-06

    authors: Kurupati P,Tan KS,Kumarasinghe G,Poh CL

    更新日期:2007-03-01 00:00:00

  • Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

    abstract::The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was sig...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.40.5.1219

    authors: Fantin B,Pierre J,Castéla-Papin N,Saint-Julien L,Drugeon H,Farinotti R,Carbon C

    更新日期:1996-05-01 00:00:00

  • Maternal-fetal pharmacology of cefatrizine in the first 20 weeks of pregnancy.

    abstract::To evaluate maternal-fetal pharmacology of cefatrizine (BL-S 640), a new oral cephalosporin, a single oral 1,000-mg dose was administered to 33 gravidas (8 to 20 weeks' gestation) at varying intervals within 46 h of an elective therapeutic abortion by hysterectomy or intra-amniotic prostaglandin F(2a) induction. Mean ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.12.2.231

    authors: Bernard B,Thielen P,Garcia-Cázares J,Ballard CA

    更新日期:1977-08-01 00:00:00

  • Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinyl macrolactin A assessed by evaluating cytochrome P450 inhibition and induction and UDP-glucuronosyltransferase inhibition in vitro.

    abstract::Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor age...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00018-14

    authors: Bae SH,Kwon MJ,Park JB,Kim D,Kim DH,Kang JS,Kim CG,Oh E,Bae SK

    更新日期:2014-09-01 00:00:00