Trichomonads, hydrogenosomes and drug resistance

Kulda, Jaroslav

doi:10.1016/s0020-7519(98)00155-6

Cited by 164 publications

(179 citation statements)

References 62 publications

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“…Ferredoxin (Fd) accepts electrons generated by PFOR. Hydrogenase (HYD) then couples electrons to hydrogen ions forming molecular hydrogen as an end product [4,29] (Fig 1). Similar metabolic pathways have been described in the ancient protozoan, G. duodenalis [4,30,31] and also in the anaerobic bacterium H. pylori [32].…”

Section: Energy Metabolismmentioning

confidence: 99%

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

et al. 2003

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Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

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Section: Energy Metabolismmentioning

confidence: 99%

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

et al. 2003

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“…This reaction is mediated by ferredoxin, which receives an electron from the pyruvate-ferredoxin oxidoreductase (PFOR) complex via conversion of pyruvate to acetyl coenzyme A (9). The resulting nitro radical anion probably causes DNA strand breaks, DNA helix destabilization, unwinding of DNA, and finally cell death (1,2,10,11), and damage to other vital cell systems is also possible (6).…”

Section: Dimetridazole (Dmz) and Tinidazole (Tnz) Mtr Is Extensivelmentioning

confidence: 99%

Structural Basis of 5-Nitroimidazole Antibiotic Resistance

Leiros¹,

Kozielski-Stuhrmann²,

Kapp

et al. 2004

Journal of Biological Chemistry

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5-Nitroimidazole-based antibiotics are compounds extensively used for treating infections in humans and animals caused by several important pathogens. They are administered as prodrugs, and their activation depends upon an anaerobic 1-electron reduction of the nitro group by a reduction pathway in the cells. Bacterial resistance toward these drugs is thought to be caused by decreased drug uptake and/or an altered reduction efficiency. One class of resistant strains, identified in Bacteroides, has been shown to carry Nim genes (NimA, -B, -C, -D, and -E), which encode for reductases that convert the nitro group on the antibiotic into a non-bactericidal amine. In this paper, we have described the crystal structure of NimA from Deinococcus radiodurans (drNimA) at 1.6 Å resolution. We have shown that drNimA is a homodimer in which each monomer adopts a ␤-barrel fold. We have identified the catalytically important His-71 along with the cofactor pyruvate and antibiotic binding sites, all of which are found at the monomer-monomer interface. We have reported three additional crystal structures of drNimA, one in which the antibiotic metronidazole is bound to the protein, one with pyruvate covalently bound to His-71, and one with lactate covalently bound to His-71. Based on these structures, a reaction mechanism has been proposed in which the 2-electron reduction of the antibiotic prevents accumulation of the toxic nitro radical. This mechanism suggests that Nim proteins form a new class of reductases, conferring resistance against 5-nitroimidazole-based antibiotics.Antibiotic resistance is an increasing problem throughout the developed world, and knowledge about different resistance mechanisms is important for efficient treatment of bacterial infections. One important class of antibiotics, the 5-nitroimidazole (5-Ni) 1 drug derivatives, includes metronidazole (MTR), dimetridazole (DMZ), and tinidazole (TNZ). MTR is extensively used in the treatment of anaerobic infections caused by Trichomonas vaginalis, Entamoeba histolytica, Enterococcus species, Giardia lamblia, Clostridium species, and Bacteroides (1-4) and is also a critical ingredient of modern multidrug therapies for Helicobacter pylori eradication regimes used to control ulcers (5). The mode of action for the 5-Ni antibiotics, as illustrated in Fig. 1, has been shown to be similar in different pathogens (6 -8). The inactive prodrug enters cells by simple diffusion and is then reduced in a 1-electron reduction into the toxic compound, the short-lived radical anion R-N⅐O 2 Ϫ . This reaction is mediated by ferredoxin, which receives an electron from the pyruvate-ferredoxin oxidoreductase (PFOR) complex via conversion of pyruvate to acetyl coenzyme A (9). The resulting nitro radical anion probably causes DNA strand breaks, DNA helix destabilization, unwinding of DNA, and finally cell death (1, 2, 10, 11), and damage to other vital cell systems is also possible (6).The success of such drugs depends on the reductive activation of the nitro group on the 5-Ni drug, which ...

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“…Substancja ta może znajdować zastosowanie głównie w przypadku rzęsistkowic przewodu pokarmowego (74). Na skutek pojawiających się lekoopornych na metronidazol i jego pochodne szczepów rzęsistków, poszukiwane są nowe leki o działaniu przeciwpierwotniaczym (55). Działanie takie na podstawie przeprowadzonych badań wykazuje nitazoksanidnowa benzamidowa pochodna nitrotiazoli.…”

Section: Diagnostykaunclassified

Systematics, biology and invasiology of trichomonads (Trichomonadida) - the current state of knowledge

Szczepaniak¹,

Tomczuk²,

Łojszczyk-Szczepaniak³

et al. 2017

Medycyna Weterynaryjna

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Trichomonads are anaerobic, flagellated protists belonging to the large phylum Parabasalia. In most cases, they exist as endosymbionts – harmless comensals of invertebrates and vertebrates – but several species are considered to be imported intestinal or urogenital parasites of humans and other animals. This paper presents current information on the taxonomy, morphology and biology of trichomonads. The characterization of invasiology followed by the description of virulence factors and pathogenic mechanisms of trichomonads is presented. The present paper also reviews diagnostic methods, treatment and prevention of trichomoniasis.

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Trichomonads, hydrogenosomes and drug resistance

Cited by 164 publications

References 62 publications

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

Structural Basis of 5-Nitroimidazole Antibiotic Resistance

Systematics, biology and invasiology of trichomonads (Trichomonadida) - the current state of knowledge

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