Mitochondria as the site of action of tetracycline on Plasmodium falciparum

Kiatfuengfoo, Rachada; Suthiphongchai, Tunagporn; Prapunwattana, Phisit; Yuthavong, Yongyuth

doi:10.1016/0166-6851(89)90002-9

Cited by 65 publications

(41 citation statements)

References 10 publications

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“…The mechanism of the antibacterial action of clindamycin is well established (reviewed by Steigbigel [15] (7). The inhibition of mitochondrial protein synthesis could result in markedly delayed antiparasitic activity if the intracellular parasites were not absolutely dependent on oxidative phosphorylation for energy but could also use glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant

Pfefferkorn

Nothnagel

Borotz

1992

Antimicrob Agents Chemother

100

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Clindamycin, which has been reported to have no significant in vitro activity against Toxoplasma gondii, actually markedly inhibits the growth of this parasite in infected human fibroblasts. When measured 3 days after treatment, the concentration required to reduce parasite growth by 50%o is about 1 ng/ml. Some observers failed to note this inhibition because of its markedly delayed onset. At 6 ng/ml, clindamycin is parasiticidal, and the rate and extent of parasite killing increase with higher drug concentrations. With the aid of chemical mutagenesis, we isolated a parasite mutant that is approximately 100-fold more resistant to clindamycin than is the wild type. Lincomycin inhibits T. gondii at a higher 50% inhibitory concentration, about 100 ng/ml. The clindamycin-resistant mutant is partially cross-resistant to lincomycin.While Derouin et al. (3) observed that clindamycin concentrations as low as 0.5 ng/ml inhibited the growth of Toxoplasma gondii, at least three other laboratories have reported that the drug has no in vitro activity (5,6,8). These latter observations are in marked contrast both to the well-established efficacy of clindamycin phosphate against toxoplasmosis in infected mice (1, 6) and to the preliminary evidence for the successful use of clindamycin phosphate to treat toxoplasmic encephalitis in AIDS patients (2). We show here that clindamycin is actually a potent parasiticidal agent in cultured cells infected with T. gondii, with a 50% inhibitory concentration (IC50) that is among the lowest reported for any antitoxoplasma drug. This activity previously escaped detection by several laboratories because the drug has little effect on parasite multiplication until many cell divisions have occurred. MATERIALS AND METHODSThe host cells for all experiments were confluent cultures of human fibroblasts that were maintained as previously described (13), except that the medium for growth contained 10% calf serum and that for infection contained 1% fetal bovine serum. The parasites were our cloned line (13) of the RH strain or mutants derived from this clone. The parasites were maintained by serial subculturing in human fibroblasts. Infected cells were disrupted by forced extrusion through a 25-gauge needle to release intracellular parasites. The newly released parasites were assayed by a plaque procedure (13). In all final experiments, this procedure was carried out with 25-cm2 flasks and the plaques were counted without staining. For preliminary plaque assays with multiwell trays, the monolayer was first fixed with 0.3 N trichloroacetic acid and then stained with Coomassie blue. Parasites were cloned by the detection of a single plaque 6 days after infection of 0.15-cm2 wells with suitably diluted suspensions of extracellular T. gondii.

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Section: Discussionmentioning

confidence: 99%

Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant

Pfefferkorn

Nothnagel

Borotz

1992

Antimicrob Agents Chemother

100

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“…If tetracycline had attained high intraparasitic concentrations, 80S ribosomal inhibition could play a role in the antimalarial effect. Tetracycline acts on mitochondria (22) and depresses the activity of dihydroorotate dehydrogenase, an iron-dependent enzyme of the pyrimidine pathway in P. falciparum (23,41), presumably due to the inhibition of enzyme protein synthesis. Doxycycline reduces the levels of malaria nucleoside 5Ј-triphosphates and deoxynucleoside 5Ј-triphosphates (58) and has shown inhibitory effects against preerythrocytic stages (28).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activities of Antibiotics against Plasmodium falciparum Are Inhibited by Iron

Pradines

Rogier

Fusaı̈

et al. 2001

Antimicrob Agents Chemother

105

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The in vitro activities of cyclines (tetracycline, doxycycline, minocycline, oxytetracycline, and rolitetracycline), macrolides (erythromycin, spiramycin, roxithromycin, and lincomycin), quinolones (norfloxacin and ofloxacin), rifampin, thiamphenicol, tobramycin, metronidazole, vancomycin, phosphomycin, and cephalosporins (cephalexin, cefaclor, cefamandole, cefuroxime, ceftriazone, cefotaxime, and cefoxitin) were evaluated on Plasmodium falciparum clones, using an isotopic, micro-drug susceptibility test. Only tetracyclines, macrolides, quinolones, and rifampin demonstrated in vitro activity against P. falciparum, which increased after a prolonged exposure (96 or 144 h). In the presence of iron (FeCl 3 ), only the activities of tetracyclines and norfloxacin were decreased. Their in vitro activity against intraerythrocytic stages of multidrug-resistant P. falciparum and their efficacy in vivo favor the use of antibiotics as antimalarial drugs. However, due to their slow antimalarial action and to the fact that they act better after prolonged contact, they probably need to be administered in conjunction with a rapidly acting antimalarial drug, such as a short course of chloroquine or quinine.

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“…The ribonucleic constituents are also considered as novel candidates for drug target of antimalarial drugs. Therefore, the new ribosomal proteins identified in this study can be potential candidates for malaria (Bottger, 2007;Clough et al, 1997;Rogers et al, 1997;Camps et al, 2002;Kiatfuengfoo et al, 1989;Yassin and Mankin, 2007;Sidhu et al, 2007). The transporter proteins in Plasmodium are yet to be exploited as drug targets and needs to be more investigated by the scientific community (Jana and Paliwal, 2007).…”

Section: (A) Cellular Componentmentioning

confidence: 99%

Annotation transfer by homology among closely related genomes helps to identify protein function in Plasmodium species

Devaraj

Chandramohan

2017

IJBRA

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Malaria is a major killer disease causing heavy loss in terms of life and medical expenditure. The genome of Plasmodium falciparum sequenced in 2002 but more than 60% of its meaning still remains unknown. We compared protein sequences from P. falciparum in the genomic sequences with P. vivax and P. knowlesi through standalone blast tool from NCBI. We found many proteins annotated in one species sharing high similarity with unannotated proteins in the other/s species. Based on the 'annotation transfer by homology' method we annotated 715 hypothetical proteins. By the latest information available as of 1st September our method annotated 343 protein sequences .Gene Ontology annotation with BLAST2GO revealed 128 proteins with Enzyme Codes among the 561 sequences mapped with GO terms. The kognitor results showed 542 proteins similar to proteins belonging to various KOG categories. More attention should be paid to these 'hypothetical' proteins as they can reveal unknown insights on the biology of organisms and have an impact in the field of drug discovery and medicine.

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Mitochondria as the site of action of tetracycline on Plasmodium falciparum

Cited by 65 publications

References 10 publications

Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant

Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant

In Vitro Activities of Antibiotics against Plasmodium falciparum Are Inhibited by Iron

Annotation transfer by homology among closely related genomes helps to identify protein function in Plasmodium species

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