Expression of the essential Kinase PfCDPK1 from Plasmodium falciparum in Toxoplasma gondii facilitates the discovery of novel antimalarial drugs.

Abstract:

:We have previously shown that genetic disruption of Toxoplasma gondii calcium-dependent protein kinase 3 (TgCDPK3) affects calcium ionophore-induced egress. We examined whether Plasmodium falciparum CDPK1 (PfCDPK1), the closest homolog of TgCDPK3 in the malaria parasite P. falciparum, could complement a TgCDPK3 mutant strain. PfCDPK1 is essential and plays critical roles in merozoite development, motility, and secretion. We show that expression of PfCDPK1 in the TgCDPK3 mutant strain rescues the egress defect. This phenotypic complementation requires the localization of PfCDPK1 to the plasma membrane and kinase activity. Interestingly, PfCDPK1-expressing Toxoplasma becomes more sensitive to egress inhibition by purfalcamine, a potent inhibitor of PfCDPK1 with low activity against TgCDPK3. Based on this result, we tested eight small molecules previously determined to inhibit the kinase activity of recombinant PfCDPK1 for their abilities to inhibit ionophore-induced egress in the PfCDPK1-expressing strain. While two of these chemicals did not inhibit egress, we found that six drugs affected this process selectively in PfCDPK1-expressing Toxoplasma. Using mutant versions of PfCDPK1 and TgCDPK3, we show that the selectivities of dasatinib and PLX-4720 are regulated by the gatekeeper residue in the ATP binding site. Importantly, we have confirmed that the three most potent inhibitors of egress in the PfCDPK1-expressing strain effectively kill P. falciparum. Thus, we have established and validated a recombinant strain of Toxoplasma that can be used as a surrogate for the discovery and analysis of PfCDPK1-specific inhibitors that can be developed as antimalarials.

authors

Gaji RY,Checkley L,Reese ML,Ferdig MT,Arrizabalaga G

doi

10.1128/AAC.02261-13

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

2598-607

issue

5

eissn

0066-4804

issn

1098-6596

pii

AAC.02261-13

journal_volume

58

pub_type

杂志文章
  • Efficacy of humanized carbapenem and ceftazidime regimens against Enterobacteriaceae producing OXA-48 carbapenemase in a murine infection model.

    abstract::Enterobacteriaceae producing the OXA-48 carbapenemase are emerging worldwide, leaving few treatment options. Efficacy has been demonstrated in vivo with ceftazidime against a ceftazidime-susceptible OXA-48 isolate but not with imipenem despite maintaining susceptibility. The relationship between phenotype and in vivo ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01947-13

    authors: Wiskirchen DE,Nordmann P,Crandon JL,Nicolau DP

    更新日期:2014-01-01 00:00:00

  • Effect of DNA gyrase inhibitors pefloxacin, five other quinolones, novobiocin, and clorobiocin on Escherichia coli topoisomerase I.

    abstract::Two coumarins, inhibitors of the B subunit of DNA gyrase, and six quinolones, inhibitors of the A subunit, were tested against Escherichia coli topoisomerase I-catalyzed DNA relaxation. Coumarins had no effect, whereas quinolones were inhibitors of the enzyme. This inhibition was compared with that of DNA gyrase and c...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.31.12.1925

    authors: Tabary X,Moreau N,Dureuil C,Le Goffic F

    更新日期:1987-12-01 00:00:00

  • Effect of rifampin on nasal carriage of Staphylococcus aureus.

    abstract::Initial studies indicate that rifampin may be useful for the treatment of Staphylococcus aureus infections. Because bacterial resistance to rifampin may develop rapidly, its widespread use could result in the emergence of a resistant flora. This study evaluates the effectiveness of rifampin in reducing the nasal carri...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.7.3.294

    authors: Sande MA,Mandell GL

    更新日期:1975-03-01 00:00:00

  • In vitro activity of the new triazole BMS-207147 against Aspergillus species in comparison with itraconazole and amphotericin B.

    abstract::The in vitro activity of BMS-207147 against 80 clinical isolates of Aspergillus was compared with that of itraconazole and amphotericin B, using a validated microtiter method. Geometric mean MICs (in microg/ml) were as follows: 1.71 for BMS-207147, 0.67 for itraconazole, and 0.63 for amphotericin B. The range of conce...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.44.2.441-443.2000

    authors: Moore CB,Walls CM,Denning DW

    更新日期:2000-02-01 00:00:00

  • Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii.

    abstract::Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of poly...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02831-15

    authors: Tsuji BT,Landersdorfer CB,Lenhard JR,Cheah SE,Thamlikitkul V,Rao GG,Holden PN,Forrest A,Bulitta JB,Nation RL,Li J

    更新日期:2016-06-20 00:00:00

  • Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans.

    abstract::Passive antibody administration is a potentially useful approach for the therapy of human Cryptococcus neoformans infections. To evaluate the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans and to construct murine antibody derivatives with reduced immunogenicities and longer half-l...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.38.7.1507

    authors: Zebedee SL,Koduri RK,Mukherjee J,Mukherjee S,Lee S,Sauer DF,Scharff MD,Casadevall A

    更新日期:1994-07-01 00:00:00

  • Target gene sequencing to define the susceptibility of Neisseria meningitidis to ciprofloxacin.

    abstract::Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of ≥ 0.064 μg/ml but not among isolates with MICs of ≤ 0.032 μg/ml. Experimental infection of cipr...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02184-12

    authors: Hong E,Thulin Hedberg S,Abad R,Fazio C,Enríquez R,Deghmane AE,Jolley KA,Stefanelli P,Unemo M,Vazquez JA,Veyrier FJ,Taha MK

    更新日期:2013-04-01 00:00:00

  • Antecedent Carbapenem Exposure as a Risk Factor for Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae and Carbapenemase-Producing Enterobacteriaceae.

    abstract::Carbapenem-resistant Enterobacteriaceae (CRE) can be mechanistically classified into carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing carbapenem nonsusceptible Enterobacteriaceae (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00845-19

    authors: Marimuthu K,Ng OT,Cherng BPZ,Fong RKC,Pada SK,De PP,Ooi ST,Smitasin N,Thoon KC,Krishnan PU,Ang MLT,Chan DSG,Kwa ALH,Deepak RN,Chan YK,Chan YFZ,Huan X,Zaw Linn K,Tee NWS,Tan TY,Koh TH,Lin RTP,Hsu LY,Sengupta

    更新日期:2019-09-23 00:00:00

  • Pharmacokinetics of the aminoglycoside antibiotic tobramycin in humans.

    abstract::The pharmacokinetics, distribution, and plasma and renal clearance of a new aminoglycoside antibiotic, tobramycin, was studied in the treatment of 18 elderly male patients (average age, 69 years) with urinary tract infections. Ten of these patients had normal renal function and eight had impaired renal function of var...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.3.4.469

    authors: Naber KG,Westenfelder SR,Madsen PO

    更新日期:1973-04-01 00:00:00

  • Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity.

    abstract::Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct pur...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.48.4.1281-1288.2004

    authors: Aubry A,Pan XS,Fisher LM,Jarlier V,Cambau E

    更新日期:2004-04-01 00:00:00

  • Antimicrobial effect of halocidin-derived peptide in a mouse model of Listeria infection.

    abstract::Halocidin is an antimicrobial peptide found in the tunicate. A series of experiments were previously conducted in an attempt to develop a novel antibiotic derived from halocidin, as the peptide was determined to evidence profound antimicrobial activity against a variety of antibiotic-resistant microbes, with significa...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00635-07

    authors: Jang WS,Lee SC,Lee YS,Shin YP,Shin KH,Sung BH,Kim BS,Lee SH,Lee IH

    更新日期:2007-11-01 00:00:00

  • Excretion of ciprofloxacin into the large bowel of the rabbit.

    abstract::The intestinal elimination of ciprofloxacin in the large bowel was studied in a rabbit model. Segments from the cecum, colon, and sigmoid colon along with their intact blood vessels were isolated and perfused, and their contents were collected over a 90-min period following the administration of a single parenteral do...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.40.1.11

    authors: Ramon J,Dautrey S,Farinoti R,Carbon C,Rubinstein E

    更新日期:1996-01-01 00:00:00

  • Activity of cefotaxime-aminoglycoside combinations against aminoglycoside-resistant Pseudomonas.

    abstract::The activity of cefotaxime, either alone or combined with an aminoglycoside, was determined against 50 isolates of Pseudomonas aeruginosa, of which 50, 33, and 10 were resistant to gentamicin, tobramycin, and amikacin, respectively. Cefotaxime inhibited 34 isolates at a concentration of 16 microgram/ml and all isolate...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.17.3.474

    authors: Murray PR

    更新日期:1980-03-01 00:00:00

  • Novel alpha- and beta-amino acid inhibitors of influenza virus neuraminidase.

    abstract::In an effort to discover novel, noncarbohydrate inhibitors of influenza virus neuraminidase we hypothesized that compounds which contain positively charged amino groups in an appropriate position to interact with the Asp 152 or Tyr 406 side chains might be bound tightly by the enzyme. Testing of 300 alpha- and beta-am...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.45.9.2563-2570.2001

    authors: Kati WM,Montgomery D,Maring C,Stoll VS,Giranda V,Chen X,Laver WG,Kohlbrenner W,Norbeck DW

    更新日期:2001-09-01 00:00:00

  • Purification of a streptococcal bacteriocin (viridin B) and its separation from alpha-hemolysin.

    abstract::Viridin B, a bacteriocin produced by Streptococcus mitis, copurified with the alpha-hemolysin after ammonium sulfate precipitation and gel filtration on Sephadex G-200. The bacteriocin and hemolysin were separated in some instances by ion-exchange chromatography on diethylaminoethyl-Sephadex A-50, but the two substanc...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.15.3.436

    authors: Apelgren LD,Dajani AS

    更新日期:1979-03-01 00:00:00

  • Efficacy of NZ2114, a novel plectasin-derived cationic antimicrobial peptide antibiotic, in experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

    abstract::Cationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungus Pseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) the in vivo...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00453-11

    authors: Xiong YQ,Hady WA,Deslandes A,Rey A,Fraisse L,Kristensen HH,Yeaman MR,Bayer AS

    更新日期:2011-11-01 00:00:00

  • Activities of Nigerian chewing stick extracts against Bacteroides gingivalis and Bacteroides melaninogenicus.

    abstract::The in vitro activities of extracts of Nigerian chewing sticks against Bacteroides gingivalis and B. melaninogenicus are presented. The greatest inhibitory action was produced by Serindeia werneckei, whereas Fagara zanthoxyloides produced no appreciable inhibitory effect. A generally good correlation was found between...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.32.4.598

    authors: Rotimi VO,Laughon BE,Bartlett JG,Mosadomi HA

    更新日期:1988-04-01 00:00:00

  • Susceptibility trends of zoliflodacin against multidrug-resistant Neisseria gonorrhoeae clinical isolates in Nanjing, China (2014-2018).

    abstract::Previously, we reported potent activity of a novel spiropyrimidinetrione, zoliflodacin, against N. gonorrhoeae isolates from symptomatic men in Nanjing, China, collected in 2013. Here, we investigated trends of susceptibilities of zoliflodacin in 986 isolates collected from men between 2014 and 2018. N. gonorrhoeae is...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00863-20

    authors: Le W,Su X,Lou X,Li X,Gong X,Wang B,Genco CA,Mueller JP,Rice PA

    更新日期:2020-12-14 00:00:00

  • Effects of ciprofloxacin on plasmid DNA supercoiling of Escherichia coli topoisomerase I and gyrase mutants.

    abstract::Changes in plasmid DNA supercoiling were measured following treatment of Escherichia coli cells, carrying topoisomerase mutations, with the quinolone ciprofloxacin. In quinolone-susceptible cells (top+ gyr+) as well as in topA mutants and in gyrB mutants, plasmid DNA was relaxed after the addition of ciprofloxacin. In...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.35.1.20

    authors: Aleixandre V,Herrera G,Urios A,Blanco M

    更新日期:1991-01-01 00:00:00

  • Effects of dihydrostreptomycin on ribosome function in vivo: lack of correlation between changes in ribosome patterns and growth.

    abstract::In vivo treatment of susceptible Escherichia coli cultures with low concentrations of dihydrostreptomycin leads to a decline in polysomes and a corresponding increase in 70S particles which behave as run-off ribosomes, as well as free 30S and 50S subunits. We have examined the timing and extent of these effects on rib...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.7.3.341

    authors: Kogut M,Prizant E

    更新日期:1975-03-01 00:00:00

  • Anti-respiratory syncytial virus (RSV) neutralizing antibody decreases lung inflammation, airway obstruction, and airway hyperresponsiveness in a murine RSV model.

    abstract::Numerous studies have described a strong association between respiratory syncytial virus (RSV) infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness. We evaluated the effect of an anti-RSV neutralizing monoclonal antibody (palivizumab) on different aspects of RSV disease by usin...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.48.5.1811-1822.2004

    authors: Mejías A,Chávez-Bueno S,Ríos AM,Saavedra-Lozano J,Fonseca Aten M,Hatfield J,Kapur P,Gómez AM,Jafri HS,Ramilo O

    更新日期:2004-05-01 00:00:00

  • Nucleotide sequences specific for Tn1545-like conjugative transposons in pneumococci and staphylococci resistant to tetracycline.

    abstract::The distributions of tet(M) and conjugative transposons related to Tn1545 were studied by hybridization in 47 clinical isolates of Streptococcus pneumoniae resistant to tetracycline. Resistance to tetracycline was always associated with resistance to minocycline and was due to the presence of the tet(M) gene. Associat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.35.8.1657

    authors: Poyart-Salmeron C,Trieu-Cuot P,Carlier C,Courvalin P

    更新日期:1991-08-01 00:00:00

  • Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates.

    abstract::The integrase inhibitor raltegravir (RAL) is currently used for the treatment of both treatment-naïve and treatment-experienced HIV-1-infected patients. Elvitegravir (EVG) is in late phases of clinical development. Since significant cross-resistance between RAL and EVG is observed, there is a need for second-generatio...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01733-09

    authors: Van Wesenbeeck L,Rondelez E,Feyaerts M,Verheyen A,Van der Borght K,Smits V,Cleybergh C,De Wolf H,Van Baelen K,Stuyver LJ

    更新日期:2011-01-01 00:00:00

  • Variety of beta-lactamases produced by amoxicillin-clavulanate-resistant Escherichia coli isolated in the northeastern United States.

    abstract::This study analyzed the enzymatic basis and molecular epidemiology of amoxicillin-clavulanate-resistant Escherichia coli isolated by the microbiology laboratory of a United States tertiary care hospital. From October 1998 to December 1999, all E. coli isolates were screened for ampicillin-sulbactam resistance. Of 283 ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.48.5.1520-1525.2004

    authors: Kaye KS,Gold HS,Schwaber MJ,Venkataraman L,Qi Y,De Girolami PC,Samore MH,Anderson G,Rasheed JK,Tenover FC

    更新日期:2004-05-01 00:00:00

  • In vitro and in vivo antibacterial activities of OPC-20011, a novel parenteral broad-spectrum 2-oxaisocephem antibiotic.

    abstract::OPC-20011, a new parenteral 2-oxaisocephem antibiotic, has an oxygen atom at the 2- position of the cephalosporin frame. OPC-20011 had the best antibacterial activities against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, and penicillin-resistant Streptoc...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.11.2943

    authors: Matsumoto M,Tamaoka H,Ishikawa H,Kikuchi M

    更新日期:1998-11-01 00:00:00

  • Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial.

    abstract::Tafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acute Plasmodium vivax malaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00711-18

    authors: Thakkar N,Green JA,Koh GCKW,Duparc S,Tenero D,Goyal N

    更新日期:2018-10-24 00:00:00

  • Efficacy of Posaconazole in a Murine Model of Systemic Infection by Saprochaete capitata.

    abstract::The fungus Saprochaete capitata causes opportunistic human infections, mainly in immunocompromised patients with hematological malignancies. The best therapy for this severe infection is still unknown. We evaluated the in vitro killing activity and the in vivo efficacy of posaconazole at 5, 10, or 20 mg/kg twice a day...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01140-15

    authors: Thomson P,Guarro J,Mayayo E,Capilla J

    更新日期:2015-12-01 00:00:00

  • A single polymorphism in HIV-1 subtype C SP1 is sufficient to confer natural resistance to the maturation inhibitor bevirimat.

    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

    authors: Lu W,Salzwedel K,Wang D,Chakravarty S,Freed EO,Wild CT,Li F

    更新日期:2011-07-01 00:00:00

  • Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus.

    abstract::Leptospirosis and scrub typhus are important causes of acute fever in Southeast Asia. Options for empirical therapy include doxycycline and azithromycin, but it is unclear whether their efficacies are equivalent. We conducted a multicenter, open, randomized controlled trial with adult patients presenting with acute fe...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1128/AAC.00508-07

    authors: Phimda K,Hoontrakul S,Suttinont C,Chareonwat S,Losuwanaluk K,Chueasuwanchai S,Chierakul W,Suwancharoen D,Silpasakorn S,Saisongkorh W,Peacock SJ,Day NP,Suputtamongkol Y

    更新日期:2007-09-01 00:00:00

  • TEM-28 from an Escherichia coli clinical isolate is a member of the His-164 family of TEM-1 extended-spectrum beta-lactamases.

    abstract::TEM-28 (pI 6.1), expressed by an Escherichia coli clinical isolate, is a novel beta-lactamase which hydrolyzed ceftazidime, cefotaxime, and aztreonam with rates of 25, 1.1, and 5.6, respectively, relative to that for benzylpenicillin (100). The nucleotide sequence of blaTEM-28 differed from that of blaTEM-1 by two bas...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.40.1.260

    authors: Bradford PA,Jacobus NV,Bhachech N,Bush K

    更新日期:1996-01-01 00:00:00