Toxoplasma gondii: Characterization of a mutant resistant to sulfonamides

Pfefferkorn, E. R.; Borotz, Susan E.; Nothnagel, Robert F.

doi:10.1016/0014-4894(92)90149-5

Cited by 33 publications

(18 citation statements)

References 12 publications

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“…These observations are in agreement with previous reports of Pfefferkorn et al (19) and Derouin and Chastang (9), who have demonstrated that sulfadiazine, dapsone, and pyrimethamine have inhibitory effects similar to those described here. In addition, our observations suggest a synergistic effect of epiroprim and dapsone on the intracellular growth of T. gondii, because ineffective concentrations of both drugs inhibited parasite multiplication when they were added simultaneously.…”

Section: Discussionsupporting

confidence: 94%

“…However, as pointed out by Pfefferkorn et al (19), in the case of sulfadiazine and dapsone, the mechanism may depend on the assumption that the final effects of these drugs are to inhibit the synthesis of dihydrofolic acid in the parasites. Thus, assuming that the intracellular parasites may contain a large supply of dihydrofolic acid, inhibition of the synthesis of dihydrofolic acid would J. not have an immediate effect on them.…”

Section: Discussionmentioning

confidence: 99%

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Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii

Chang

Arsenijevic

Comte

et al. 1994

Antimicrob Agents Chemother

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We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 104 parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0%o of the mice, respectively. When these drugs were administered simultaneously, a 100%o survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kgJday, respectively) protected 100%1v of the mice. A 3-week therapy of chronically infected mice with either epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine (15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii

Chang

Arsenijevic

Comte

et al. 1994

Antimicrob Agents Chemother

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“…Other authors arbitrarily used an eightfold increase in the inhibitory concentration compared to that of sensitive strains (15). For SDZ and atovaquone, no criterion has been defined, but resistant mutants obtained by mutagenesis have IC 50 s that are 20-to 300-fold higher than that of the wild type (6,38,39).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Up to now, very few data document the two latter hypotheses. Drug-resistant mutants have been obtained in vitro by mutagenesis under drug pressure for sulfonamides (38), pyrimethamine (41,42), and atovaquone (32,39). However, the demonstration of a mutation responsible for substantial resistance to sulfonamides was demonstrated for only one clinical isolate (6).…”

mentioning

confidence: 99%

In Vitro Susceptibility of Various Genotypic Strains of Toxoplasma gondii to Pyrimethamine, Sulfadiazine, and Atovaquone

Méneceur

Bouldouyre

Aubert

et al. 2008

Antimicrob Agents Chemother

128

115

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Sulfadiazine, pyrimethamine, and atovaquone are widely used for the treatment of severe toxoplasmosis. Their in vitro activities have been almost exclusively demonstrated on laboratory strains belonging to genotype I. We determined the in vitro activities of these drugs against 17 strains of Toxoplasma gondii belonging to various genotypes and examined the correlations among 50% inhibitory concentrations (IC 50 s), growth kinetics, strain genotypes, and mutations on drug target genes. Growth kinetics were determined in THP-1 cell cultures using real-time PCR. IC 50 s were determined in MRC-5 cell cultures using a T. gondii-specific enzyme-linked immunosorbent assay performed on cultures. Mutations in dihydrofolate reductase (DHFR), dihydropteroate synthase (DHPS), and cytochrome b genes were determined by sequencing. Pyrimethamine IC 50 s ranged between 0.07 and 0.39 mg/liter, with no correlation with the strain genotype but a significant correlation with growth kinetics. Several mutations found on the DHFR gene were not linked to lower susceptibility. Atovaquone IC 50 s were in a narrow range of concentrations (mean, 0.06 ؎ 0.02 mg/liter); no mutation was found on the cytochrome b gene. IC 50 s for sulfadiazine ranged between 3 and 18.9 mg/liter for 13 strains and were >50 mg/liter for three strains. High IC 50 s were not correlated to strain genotypes or growth kinetics. A new mutation of the DHPS gene was demonstrated in one of these strains. In conclusion, we found variability in the susceptibilities of T. gondii strains to pyrimethamine and atovaquone, with no evidence of drug resistance. A higher variability was found for sulfadiazine, with a possible resistance of three strains. No relationship was found between drug susceptibility and strain genotype.

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“…The enzyme dihydropteroate synthase (DHPS; EC 2.5.1.15) catalyzes the formation of dihydropteroic acid in bacterial and some eucaryotic cells, like Pneumocystis carinii (179), Toxoplasma gondii (123), and Plasmodium falciparum (192). This enzyme activity is not present in human cells.…”

Section: Mechanisms Of Resistancementioning

confidence: 99%