Mitochondrial Electron Transport Chain of Plasmodium falciparum

Fisher, Nicholas; Antoine, Thomas; Ward, Stephen A.; Biagini, Giancarlo A.

doi:10.1007/978-1-4614-8757-9_12-1

Cited by 4 publications

(3 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pf and Mtb also contain other flavoenzymes (diaphorases) including the essential respiratory enzymes Type II NADH:quinone oxidoreductases (NDH-2) that induce electron transfer from NADH to the cofactor FADt om enaquinone in the respiratory chain. [26] These are potentially susceptible to electron-scavenging by the same redox-oxidant drug combinations.A dditional drug components added to the drug mixtures are also required on the basis of enhancing efficacy through enabling activity against ad ifferent target, and suppressing the emergence of resistantpathogens.…”

Section: Introductionmentioning

confidence: 99%

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

View full text Add to dashboard Cite

To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.

show abstract

Section: Introductionmentioning

confidence: 99%

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The hydrophobic subunit of cytochrome b is an essential component of the cyt bc 1 complex, which functions as a proton-motive ubiquinol [42] and plays a crucial role in oxidizing ubiquinol (QH 2 ) to ubiquinone (Q) and donating electrons to cytochrome c oxidase. In parasitic protozoa, including E. tenella, dihydroorotate dehydrogenase (DHODH) also acts as an essential enzyme for the de novo synthesis of pyrimidines, which is the exclusive pathway to synthesize pyrimidines [43,44]. However, the addition of uracil to the medium did not have a substantial effect on the in vitro anti-parasite activity of decoquinate, suggesting that de novo pyrimidine synthesis was not the primary biochemical target of decoquinate in T. gondii [35].…”

Section: Discussionmentioning

confidence: 99%

Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella

Hao

Chen

Sun

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Protozoan parasites of the genus Eimeria are the causative agents of chicken coccidiosis. Parasite resistance to most anticoccidial drugs is one of the major challenges in controlling this disease. There is an urgent need for a molecular marker to monitor the emergence of resistance against anticoccidial drugs, such as decoquinate. Methods In this study, we developed decoquinate-resistant strains by successively exposing the Houghton (H) and Xinjiang (XJ) strains of E. tenella to incremental concentrations of the drug in chickens. Additionally, we isolated a decoquinate-resistant strain from the field. The resistance of these three strains was tested using the criteria of weight gain (WG), relative oocyst production (ROP), and reduction of lesion scores (RLS). Whole-genome sequencing was used to identify the non-synonymous mutations in coding genes that were highly associated with the decoquinate-resistant phenotype in the two laboratory-induced strains. Subsequently, we further scrutinized the missense mutation in a field-resistant strain for verification. We employed AlphaFold and PyMOL to model the alterations in the binding affinity of the mutants towards the drug molecule. Results We obtained two decoquinate-resistant strains, DecR_H and XJ, originating from the H and XJ strains, respectively, as well as a field-resistant E. tenella strain, DecR_SC. These three strains displayed resistant to 120 mg/kg decoquinate administered through feed. Through whole-genome sequencing analysis, we identified the cytochrome b gene (ETH2_MIT00100) as the sole mutated gene shared between the DecR_H and XJ strains and was also detected in the DecR_SC strain. Distinct non-synonymous mutations, namely Gln131Lys in the DecR_H, Phe263Leu in the DecR_XJ, and Phe283Leu in the DecR_SC were observed in the three resistant strains. Notably, these mutations were located in the extracellular segment of cytochrome b, in close proximity to the ubiquinol oxidation site Qo. Drug molecular docking studies revealed that these mutants exhibited varying degrees of reduced binding ability to decoquinate. Conclusions Our findings emphasize the critical role of cytochrome b mutations in the development of decoquinate resistance in E. tenella. The strong correlation observed between cytochrome b mutant alleles and resistance indicates their potential as valuable molecular markers for the rapid detection of decoquinate resistance.

show abstract

“…The hydrophobic subunit of cytochrome b is an essential component of the cyt bc 1 complex, which functions as a proton-motive ubiquinol [ 44 ] and plays a crucial role in oxidizing ubiquinol (QH 2 ) to ubiquinone (Q) and donating electrons to cytochrome c oxidase. In parasitic protozoa, including E. tenella , dihydroorotate dehydrogenase (DHODH) also acts as an essential enzyme for the de novo synthesis of pyrimidines, which is the exclusive pathway to synthesize pyrimidines [ 45 , 46 ]. However, in one study, the addition of uracil to the medium did not have a substantial effect on the in vitro anti-parasite activity of decoquinate, suggesting that de novo pyrimidine synthesis was not the primary biochemical target of decoquinate in T. gondii [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella

Hao,

Chen,

Sun

et al. 2023

Parasites Vectors

View full text Add to dashboard Cite

Background Protozoan parasites of the genus Eimeria are the causative agents of chicken coccidiosis. Parasite resistance to most anticoccidial drugs is one of the major challenges to controlling this disease. There is an urgent need for a molecular marker to monitor the emergence of resistance against anticoccidial drugs, such as decoquinate. Methods We developed decoquinate-resistant strains by successively exposing the Houghton (H) and Xinjiang (XJ) strains of E. tenella to incremental concentrations of this drug in chickens. Additionally, we isolated a decoquinate-resistant strain from the field. The resistance of these three strains was tested using the criteria of weight gain, relative oocyst production and reduction of lesion scores. Whole-genome sequencing was used to identify the non-synonymous mutations in coding genes that were highly associated with the decoquinate-resistant phenotype in the two laboratory-induced strains. Subsequently, we scrutinized the missense mutation in a field-resistant strain for verification. We also employed the AlphaFold and PyMOL systems to model the alterations in the binding affinity of the mutants toward the drug molecule. Results We obtained two decoquinate-resistant (DecR) strains, DecR_H and XJ, originating from the original H and XJ strains, respectively, as well as a decoquinate-resistant E. tenella strain from the field (DecR_SC). These three strains displayed resistance to 120 mg/kg decoquinate administered through feed. Through whole-genome sequencing analysis, we identified the cytochrome b gene (cyt b; ETH2_MIT00100) as the sole mutated gene shared between the DecR_H and XJ strains and also detected this gene in the DecR_SC strain. Distinct non-synonymous mutations, namely Gln131Lys in DecR_H, Phe263Leu in DecR_XJ, and Phe283Leu in DecR_SC were observed in the three resistant strains. Notably, these mutations were located in the extracellular segments of cyt b, in close proximity to the ubiquinol oxidation site Qo. Drug molecular docking studies revealed that cyt b harboring these mutants exhibited varying degrees of reduced binding ability to decoquinate. Conclusions Our findings emphasize the critical role of cyt b mutations in the development of decoquinate resistance in E. tenella. The strong correlation observed between cyt b mutant alleles and resistance indicates their potential as valuable molecular markers for the rapid detection of decoquinate resistance. Graphical abstract

show abstract

Mitochondrial Electron Transport Chain of Plasmodium falciparum

Cited by 4 publications

References 53 publications

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella

Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella

Contact Info

Product

Resources

About