Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis

RASOLOSON, Dominique; Štěpánka VAŇÁČOVÁ; Eva TOMKOVA; Jakub RAZGA; Ivan HRDY; Jan TACHEZY a Jaroslav KULDA. Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis. Microbiology-UK. 2002, roč. 148, č. 8, s. 2467-2477. ISSN 1350-0872.

Základní údaje

Originální název

Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis

Název česky

Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis

Autoři

RASOLOSON, Dominique; Štěpánka VAŇÁČOVÁ; Eva TOMKOVA; Jakub RAZGA; Ivan HRDY; Jan TACHEZY a Jaroslav KULDA

Vydání

Microbiology-UK, 2002, 1350-0872

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Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 2.897

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/02:00036243

Organizační jednotka

Přírodovědecká fakulta

UT WoS

000177529800024

Klíčová slova česky

Trichomonas; hydrogenosome; metronidazole; ferredoxin; PFOR; malic enzyme

Klíčová slova anglicky

Trichomonas; hydrogenosome; metronidazole; ferredoxin; PFOR; malic enzyme

Štítky

ferredoxin, hydrogenosome, malic enzyme, metronidazole, PFOR, Trichomonas

Příznaky

Mezinárodní význam, Recenzováno

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Anotace

V originále

Development of resistance against metronidazole and mechanisms responsible for this process were studied in a sexually transmitted pathogen of humans, Trichomonas vaginalis. Monitoring of changes in metabolism and protein expression that accompanied increasing resistance of strains derived from a common drug-susceptible parent (TV 10-02) showed the multistep character of the process. The aerobic type of resistance known to occur in isolates from patients non-responsive to treatment appeared at the earliest stage, followed by development of the anaerobic type of resistance which was accompanied by gradual loss of hydrogenosomal proteins associated with drug-activating pathways [pyruvate:ferredoxin oxidoreductase (PFOR), hydrogenase, ferredoxin]. Unexpectedly, the loss of PFOR did not result in acquisition of full anaerobic resistance, thus indicating an alternative source of electrons required for the drug activation. These data suggest involvement of the oxidative decarboxylation of malate in hydrogenosomes, catalysed by NAD(+)-dependent malic enzyme and subsequent transfer of reduced equivalents to the drug via NADH:ferredoxin oxidoreductase and ferredoxin. Accordingly, all components of this pathway were eliminated before the resistance was fully developed. Resistant Trichomonas vaginalis compensated the impaired function of hydrogenosomes by enhanced conversion of pyruvate to lactate in the cytosol. Further analysis of the two key enzymes involved in metronidazole activation by Northern blotting and assay for nascent mRNA showed that the insufficient expression of the PFOR protein results from decreased gene transcription, while down-regulation of malic enzyme is controlled at the mRNA level.

Česky

Development of resistance against metronidazole and mechanisms responsible for this process were studied in a sexually transmitted pathogen of humans, Trichomonas vaginalis. Monitoring of changes in metabolism and protein expression that accompanied increasing resistance of strains derived from a common drug-susceptible parent (TV 10-02) showed the multistep character of the process. The aerobic type of resistance known to occur in isolates from patients non-responsive to treatment appeared at the earliest stage, followed by development of the anaerobic type of resistance which was accompanied by gradual loss of hydrogenosomal proteins associated with drug-activating pathways [pyruvate:ferredoxin oxidoreductase (PFOR), hydrogenase, ferredoxin]. Unexpectedly, the loss of PFOR did not result in acquisition of full anaerobic resistance, thus indicating an alternative source of electrons required for the drug activation. These data suggest involvement of the oxidative decarboxylation of malate in hydrogenosomes, catalysed by NAD(+)-dependent malic enzyme and subsequent transfer of reduced equivalents to the drug via NADH:ferredoxin oxidoreductase and ferredoxin. Accordingly, all components of this pathway were eliminated before the resistance was fully developed. Resistant Trichomonas vaginalis compensated the impaired function of hydrogenosomes by enhanced conversion of pyruvate to lactate in the cytosol. Further analysis of the two key enzymes involved in metronidazole activation by Northern blotting and assay for nascent mRNA showed that the insufficient expression of the PFOR protein results from decreased gene transcription, while down-regulation of malic enzyme is controlled at the mRNA level.