Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica

Samarawickrema, Nirma; Brown, David; Upcroft, Jacqueline; Thammapalerd, Nitaya; Upcroft, Peter

doi:10.1093/jac/40.6.833

Cited by 139 publications

(97 citation statements)

References 42 publications

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“…Many of the glycolytic enzymes are reversible (127,158) and utilize the energy of the pyrophosphate bond, not ATP. To date, only one 2-oxoacid oxidoreductase, PFOR, has been detected in Entamoeba, and it is predominantly membrane bound (167,189,216 ϩ (catalyzed by putative ferredoxin:NAD oxidoreductase), regenerating intracellular pools of NAD(P)H and oxidized ferredoxin. In the process of ferredoxin reduction, acetyl-CoA is generated from pyruvate and reduced CoA (CoASH).…”

Section: Entamoeba Metabolismmentioning

confidence: 99%

“…189). Unlike Giardia, Entamoeba produces SOD, and two different SOD activities have been detected (167). Entamoeba lacks glutathione reductase activity and does not synthesize glutathione (57).…”

Section: Entamoeba Metabolismmentioning

confidence: 99%

“…Indeed, using stepwise incremental increases in drug dose, we have induced metronidazole resistance in two axenic lines of E. histolytica (167). Parasites of strains HM-I:IMSS (isolated from a rectal ulcer from an adult male in Mexico City in 1967) and HTH-56:MUTM (established in culture from an amoebic abscess from an adult in Bangkok in 1992) currently grow in our laboratory in 10 M metronidazole, a concentration of drug which is normally lethal to parasites in vitro (68).…”

Section: Entamoeba Drug Treatment and Resistancementioning

confidence: 99%

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Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

2001

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The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance

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Section: Entamoeba Metabolismmentioning

confidence: 99%

Section: Entamoeba Metabolismmentioning

confidence: 99%

Section: Entamoeba Drug Treatment and Resistancementioning

confidence: 99%

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Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

2001

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“…Amebic POR and ADHE, which also lack signal sequences or organelle-targeting presequences, have been found on the surface of amebae and in one report in organelles (POR) (8,38,41,43,55). How amebic POR and ADHE get to these locations is not clear.…”

Section: Resultsmentioning

confidence: 99%

Hsp60 Is Targeted to a Cryptic Mitochondrion-Derived Organelle (“Crypton”) in the Microaerophilic Protozoan Parasite Entamoeba histolytica

Mai¹,

Ghosh²,

Frisardi³

et al. 1999

Molecular and Cellular Biology

173

113

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Entamoeba histolytica is a microaerophilic protozoan parasite in which neither mitochondria nor mitochondrion-derived organelles have been previously observed. Recently, a segment of an E. histolytica gene was identified that encoded a protein similar to the mitochondrial 60-kDa heat shock protein (Hsp60 or chaperonin 60), which refolds nuclear-encoded proteins after passage through organellar membranes. The possible function and localization of the amebic Hsp60 were explored here. Like Hsp60 of mitochondria, amebic Hsp60 RNA and protein were both strongly induced by incubating parasites at 42°C. 5 and 3 rapid amplifications of cDNA ends were used to obtain the entire E. histolytica hsp60 coding region, which predicted a 536-aminoacid Hsp60. The E. histolytica hsp60 gene protected from heat shock Escherichia coli groEL mutants, demonstrating the chaperonin function of the amebic Hsp60. The E. histolytica Hsp60, which lacked characteristic carboxy-terminal Gly-Met repeats, had a 21-amino-acid amino-terminal, organelle-targeting presequence that was cleaved in vivo. This presequence was necessary to target Hsp60 to one (and occasionally two or three) short, cylindrical organelle(s). In contrast, amebic alcohol dehydrogenase 1 and ferredoxin, which are bacterialike enzymes, were diffusely distributed throughout the cytosol. We suggest that the Hsp60-associated, mitochondrion-derived organelle identified here be named "crypton," as its structure was previously hidden and its function is still cryptic.

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“…Additionally, metronidazole resistance has been documented in clinical isolates of Giardia intestinalis and Trichomonas vaginalis and has been artificially induced in a laboratory strain of E. histolytica , 12,13 although resistance has not been seen clinically.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Antiamebic Drugs in a Mouse Model

Becker¹,

Hoffman²,

Houpt³

2011

The American Society of Tropical Medicine and Hygiene

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Nitroimidazole antibiotics are the mainstay of treatment of invasive amebiasis; however, few comparative studies of applicable antibiotics are available. Evidence of sporadic clinical failure and rare reports of metronidazole resistance have led to the investigation of novel antiamebic therapeutics. The goal of this study was to examine drug efficacy in both in vitro and in vivo models of intestinal amebiasis. We studied six current and three novel drugs. Many drugs, including metronidazole, nitazoxanide, and nitazoxanide derivatives, were shown to be potently inhibitory in vitro. However, metronidazole remained the most effective in vivo, both in preventative and curative regimens, underscoring the value of animal models in evaluating future therapies.

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Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica

Cited by 139 publications

References 42 publications

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

Hsp60 Is Targeted to a Cryptic Mitochondrion-Derived Organelle (“Crypton”) in the Microaerophilic Protozoan Parasite Entamoeba histolytica

Efficacy of Antiamebic Drugs in a Mouse Model

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