Metronidazole resistance of Trichomonas vaginalis as a cause of treatment failure in trichomoniasis--A case report.

Kulda, Jaroslav; Vojtechovska, M; Tachezy, Jan; Demĕs, P; Kunzova, Eva

doi:10.1136/sti.58.6.394

Cited by 30 publications

(25 citation statements)

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“…Resistance to metronidazole and related 5-nitroimidazole drugs has been demonstrated both in field isolates of Trichomonas vaginalis from patients refractory to treatment (Kulda et al, 1982 ;Lossick et al, 1986 ;Meingassner & Thurner, 1979 ;Meri et al, 2000 ;Mu$ ller et al, 1980) and in laboratory-developed strains obtained by exposing trichomonads to sublethal pressure of the drug either in vitro (Brown et al, 1999 ;Kulda et al, 1984Kulda et al, , 1993Tachezy et al, 1993) or in vivo (de Carneri et al, 1969 ;Meingassner et al, 1978). Two distinct types of resistance have been recognized and named aerobic and anaerobic according to conditions required for demonstration of resistance by susceptibility assays in vitro (Kulda, 1999).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalisDominique Rasoloson, SB te) pa! nka Van) a! c) ova! , Eva Tomkova! , Jakub Ra! zga, Ivan Hrdy! , Jan Tachezy and Jaroslav Kulda 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 Mdependent 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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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“…Trichomonas vaginalis strain TV 10-02, which is susceptible to metronidazole (9), and its laboratory-induced derivatives lacking PFOR activity, which express low (TV 10-02 MR 5) or high (TV 10-02 MR 100) levels of metronidazole resistance (8,17), were used in the experiments monitoring the formation of metronidazole anion radicals by isolated hydrogenosomes. T. vaginalis strain T1 (provided by Patricia Johnson, University of California, Los Angeles, Calif.) was used for the purification of NDH.…”

Section: Organismsmentioning

confidence: 99%

Alternative Pathway of Metronidazole Activation inTrichomonas vaginalisHydrogenosomes

Hrdý

Cammack

Stopka

et al. 2005

Antimicrob Agents Chemother

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Metronidazole and related 5-nitroimidazoles are the only available drugs in the treatment of human urogenital trichomoniasis caused by the protozoan parasite Trichomonas vaginalis. The drugs are activated to cytotoxic anion radicals by their reduction within the hydrogenosomes. It has been established that electrons required for metronidazole activation are released from pyruvate by the activity of pyruvate:ferredoxin oxidoreductase and transferred to the drug by a low-redox-potential carrier, ferredoxin. Here we describe a novel pathway involved in the drug activation within the hydrogenosome. The source of electrons is malate, another major hydrogenosomal substrate, which is oxidatively decarboxylated to pyruvate and CO 2 by NAD-dependent malic enzyme. The electrons released during this reaction are transferred from NADH to ferredoxin by NADH dehydrogenase homologous to the catalytic module of mitochondrial complex I, which uses ferredoxin as electron acceptor. Trichomonads acquire high-level metronidazole resistance only after both pyruvate-and malate-dependent pathways of metronidazole activation are eliminated from the hydrogenosomes.For more than 40 years, metronidazole and related derivatives of 5-nitroimidazole have been the drugs of choice in the treatment of infections caused by anaerobic or microaerophilic microbes, both prokaryotic and eukaryotic. The susceptible organisms are characterized by the presence of low-redoxpotential electron-transporting systems that are absent in aerobes. These pathways involve ferredoxin-like electron carriers that use the nitroimidazole prodrugs as electron acceptors, generating short-lived reactive anion radicals that inflict multiple types of cellular damage and subsequent cell death (5, 14).In Trichomonas vaginalis, an amitochondriate flagellate causing human urogenital trichomoniasis, metronidazole is activated within hydrogenosome. This double-membrane-bound organelle harbors a catabolic pathway in which pyruvate or malate is oxidatively decarboxylated with concomitant generation of electrons. Pyruvate is converted to acetyl coenzyme A (acetyl-CoA) and CO 2 by a pyruvate:ferredoxin oxidoreductase (PFOR). While acetyl-CoA is utilized in a substrate-level synthesis of ATP, the released electrons are transferred via ferredoxin to hydrogenase that produces molecular hydrogen (15). Malate is converted to pyruvate and CO 2 by malic enzyme. The electrons released from malate reduce NAD ϩ , from which they are transferred to ferredoxin by NADH:ferredoxin oxidoreductase activity (17) of the NADH dehydrogenase (NDH) module of complex I (6). Metronidazole enters the hydrogenosomes by diffusion and acts as a high-affinity electron acceptor, which is reduced by ferredoxin to its cytotoxic form (7). PFOR-dependent generation of electrons is considered to be the key pathway responsible for the metronidazole activation, although a low-level NADH-dependent activity-reducing metronidazole, which was not studied in more detail, was observed in the bovine parasite Tritrichomonas foet...

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“…Moreover, infections are linked to cervical cancer (15,16,17,18), benign prostate hyperplasia (19), advanced prostate cancer (20,21,22), and an increased risk of HIV infection (23,24,25,26,27). The increased recognition of the severe risks possible from a T. vaginalis infection along with reports of drug-resistant infections (28,29,30) underscores the need for a more complete understanding of host-pathogen interactions with a focus on differences between male and female infections.Despite the severe consequences that can arise from trichomoniasis, the mechanisms underlying the establishment and propagation of an infection are poorly understood, even less so in the male than in the female host. T. vaginalis is an extracellular parasite that does not become internalized by the host cell.…”

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confidence: 99%

Trichomonas vaginalis Contact-Dependent Cytolysis of Epithelial Cells

et al. 2013

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bTrichomonas vaginalis is an extracellular protozoan parasite that binds to the epithelium of the human urogenital tract during infection. In this study, we examined the propensities of 26 T. vaginalis strains to bind to and lyse prostate (BPH-1) and ectocervical (Ect1) epithelium and to lyse red blood cells (RBCs). We found that only three of the strains had a statistically significant preference for either BPH-1 (MSA1103) or Ect1 (LA1 and MSA1123). Overall, we observed that levels of adherence are highly variable among strains, with a 12-fold range of adherence on Ect1 cells and a 45-fold range on BPH-1 cells. Cytolysis levels displayed even greater variability, from no detectable cytolysis to 80% or 90% cytolysis of Ect1 and BPH-1, respectively. Levels of adherence and cytolysis correlate for weakly adherent/cytolytic strains, and a threshold of attachment was found to be necessary to trigger cytolysis; however, this threshold can be reached without inducing cytolysis. Furthermore, cytolysis was completely blocked when we prevented attachment of the parasites to host cells while allowing soluble factors complete access. We demonstrate that hemolysis was a rare trait, with only 4 of the 26 strains capable of lysing >20% RBCs with a 1:30 parasite/RBC ratio. Hemolysis also did not correlate with adherence to or cytolysis of either male (BPH-1)-or female (Ect1)-derived epithelial cell lines. Our results reveal that despite a broad range of pathogenic properties among different T. vaginalis strains, all strains show strict contact-dependent cytolysis. T he exclusively human-infective flagellated parasitic protistTrichomonas vaginalis is the cause of the most common nonviral sexually transmitted disease, trichomoniasis. In women, the parasite resides in the vagina and colonizes the cervix; in men, it can be found in the urogenital tract and the prostate. In 2008 alone there were an estimated 276.4 million new cases in adults between 19 and 49 years of age, with a 10-fold-higher prevalence in females than in males (1). T. vaginalis in males often goes undetected, and thus the incidence is difficult to determine. However, it has been reported that in men with infected female partners, the incidence can range from 15 to 73% (2, 3, 4, 5). Additionally, men can clear infections 3 to 12 times faster than women whether the infection is treated or not (6, 7). The percentage of men who reportedly remain asymptomatic upon T. vaginalis infection is highly variable depending on the population examined and the diagnostic technique utilized. Regardless, it is thought that a higher proportion of men than women have asymptomatic infections (4,8,9).T. vaginalis infection can cause symptoms ranging from irritation and swelling in the urogenital tract to severe complications such as cervical erosion and premature birth during pregnancy (10,11,12). Trichomoniasis is also associated with infertility in both men and women (13,14). Moreover, infections are linked to cervical cancer (15,16,17,18), benign prostate hyperplasia (19), advance...

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Metronidazole resistance of Trichomonas vaginalis as a cause of treatment failure in trichomoniasis--A case report.

Cited by 30 publications

References 21 publications

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

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

Alternative Pathway of Metronidazole Activation inTrichomonas vaginalisHydrogenosomes

Trichomonas vaginalis Contact-Dependent Cytolysis of Epithelial Cells

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