Assay Conditions and the Demonstration of Nitroimidazole Resistance in
            <i>Tritrichomonas foetus</i>

Meingassner, Josef G.; Mieth, H.; Czok, R.; Lindmark, Donald G.; Müller, Miklós

doi:10.1128/aac.13.1.1

Cited by 70 publications

(34 citation statements)

References 11 publications

(11 reference statements)

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“…DISCUSSION T. vaginalis IR-78 was isolated from a patient who did not respond to normal therapy with metronidazole. The strain exhibited metronidazole resistance in vitro only under aerobic conditions, thus confirming our earlier suggestion that in vitro assay conditions can play a decisive role in identifying resistant strains of T. vaginalis (18). Since microaerophilic conditions exist in the tube test used, it appears to be an undesirable technique in studying this problem.…”

Section: Resultssupporting

confidence: 82%

Strain of Trichomonas vaginalis Resistant to Metronidazole and Other 5-Nitroimidazoles

Meingassner

Thurner

1979

Antimicrob Agents Chemother

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138

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A strain of Trichomonas vaginalis , recently isolated from a patient afflicted with recurrent symptomatic trichomoniasis, showed resistance to metronidazole, tinidazole, and nimorazole in vitro as well as in vivo. In a serial dilution test using cysteine monohydrochloride-peptone-liver infusion-maltose medium, T. vaginalis IR-78 was only resistant under aerobic conditions. Under anaerobic conditions it was as susceptible as the normal reference strain. The minimal lethal concentrations of metronidazole, tinidazole, and nimorazole for IR-78 were 100, 50, and 50 ,ug/ml aerobically and 0.4,0.4, and 0.2 ,g/ml anaerobically, respectively.The efficacy of metronidazole, tinidazole, and nimorazole was assessed in vivo by oral administration to mice simultaneously infected with IR-78 both subcutaneously and intraperitoneally. The CD5o (dose needed to cure 50% of infections) of each compound was significantly higher for the subcutaneous than for the intraperitoneal infection. In contrast, there was little difference in CD50 for these infections in mice inoculated with a susceptible trichomonas strain. The CD50's for all three compounds against intraperitoneal and subcutaneous infections with IR-78 were 2 to >70 times higher than for susceptible strain E. Both forms of infection with IR-78 could always be cured with therapeutically acceptable doses of tinidazole and nimorazole; subcutaneous infections could not be cured with tolerated doses of metronidazole.

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Section: Resultssupporting

confidence: 82%

Strain of Trichomonas vaginalis Resistant to Metronidazole and Other 5-Nitroimidazoles

Meingassner

Thurner

1979

Antimicrob Agents Chemother

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138

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“…Untreated and DMSO-and metronidazole-treated cultures served as controls. Cell density was determined by counting motile cells using a hemocytometer as previously described (27). Bioactivity was determined in five separate experiments and expressed as the percentage of dead parasites relative to the number in DMSO-treated cultures.…”

Section: Methodsmentioning

confidence: 99%

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro

Caffrey

Steverding

Swenerton

et al. 2007

Antimicrob Agents Chemother

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Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bisacridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC 50 ) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low-to mid-nanomolar EC 50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

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“…vaginalis strains TV10-02 and MR-100 were generously provided by Dr J. Tachezy . Values for metronidazole susceptibility (Meingassner et al, 1978;Müller et al, 1988) were compiled from the values in the references. Trt.…”

Section: Methodsmentioning

confidence: 99%

“…The indophenol colorimetric method of Berthelot (1859) cited in Chaney & Marbach (1962) and modified by Weatherburn (1967) was used to determine the amounts of ammonium ions (NH Soluble ammonium (NH z 4 and NH 3 ) was measured by placing a 5 ml sample of the liquid from overnight cultures in a sealed glass scintillation vial that contained a wick moistened with (20 mM) sulfuric acid to trap ammonium released by the addition of 2?5 mM boric acid pH 9?5 and subsequently incubated overnight at room Meingassner et al (1978) and Kulda et al (1993), except for strain RU393. Resistance is defined as minimum lethal concentration, >100 mg metronidazole (ml TYM medium)…”

Section: Methodsmentioning

confidence: 99%

Production of ammonia by Tritrichomonas foetus and Trichomonas vaginalis

2004

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Production of ammonia is difficult to find among the various studies of amino acid metabolism in protozoa. Several studies suggest that catabolism of arginine to ammonium is important for the growth of trichomonads. Trichomonads are amitochondriate zooflagellates that thrive under microaerophilic and anaerobic conditions. The authors were able to detect accumulation of ammonium ions and ammonia in cultures of Tritrichomonas foetus and Trichomonas vaginalis, including those resistant to metronidazole. Ammonium ions and ammonia were detected using the indophenol colorimetric method. Cells incubated overnight under an ambient oxygen gas phase had 0?9 mM soluble ammonium (NH 4 + and NH 3 ) or a 20 % greater concentration of ammonium relative to sterile growth medium that had been incubated similarly. Production of ammonia itself was confirmed by analysis of a wick that was moistened with sulfuric acid (20 mM) and placed above the liquid in sealed cultures of a strain of Trichomonas vaginalis. The wicks from these cultures captured the equivalent of 0?048 mM volatile ammonia (NH 3 ) from the liquid as compared to 0?021 mM volatile ammonia from sterile medium after overnight incubation. Intact trichomonads, 0?7610 6 cells ml "1 equivalent to 0?7 mg protein ml, incubated in Doran's buffer with or without (1 mM) L-arginine produced significant amounts of soluble ammonium (0?07 mM and 0?04 mM, respectively) during 60 min. The results indicate that ammonium ions and the more irritating ammonia are significant metabolites of trichomonads. In addition, based upon end-product amounts, it appears that the rate of arginine metabolism is of the same order of magnitude as that for carbohydrate metabolism by trichomonads.

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Assay Conditions and the Demonstration of Nitroimidazole Resistance in Tritrichomonas foetus

Cited by 70 publications

References 11 publications

Strain of Trichomonas vaginalis Resistant to Metronidazole and Other 5-Nitroimidazoles

Strain of Trichomonas vaginalis Resistant to Metronidazole and Other 5-Nitroimidazoles

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro

Production of ammonia by Tritrichomonas foetus and Trichomonas vaginalis

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