Physiological and proteomic profiles of Trypanosoma brucei rhodesiense parasite isolated from suramin responsive and non-responsive HAT patients in Busoga, Uganda

Bateta, Rosemary; Rono, Martin K.; Njunge, James M.; Awuoche, Erick O.; Ndung’u, Kariuki; Mang’era, Clarence M.; Akoth, Modesta O.; Adung’a, Vincent O.; Ondigo, Bartholomew N.; Mireji, Paul O.

doi:10.1016/j.ijpddr.2021.02.001

Cited by 4 publications

(4 citation statements)

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“…Melarsoprol resistance in Uganda and Tanzania has also been associated with mutations in the Tb AT1 gene [ 57 ]. In DRC, melarsoprol alone is no longer used in late-stage HAT [ 58 ] and has been substituted with eflornithine for this stage [ 59 ]. The increasing levels of HATr have led to the promotion of combination therapy [ 60 ], as well as increased capital to invest in the discovery of more potent drugs superior those currently on the market.…”

Section: Resultsmentioning

confidence: 99%

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

2022

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Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0–91.6); I2 = 96.99% (95% CI: 94.6–98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94–59.09) and 6.56% (3.06–11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.

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Section: Resultsmentioning

confidence: 99%

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

2022

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“…It has not been determined if VSG13 and other VSGs that fall within this structural grouping also possess suramin-binding capabilities or if they serve as determinants for suramin resistance when presented at the trypanosomal cell surface. A study of trypanosomes obtained from suramin responsive and non-responsive HAT patients attempted to elucidate the underlying proteomic profiles of resistant trypanosomes [114]. The trypanosomes isolated from the non-responsive patients (T. b. rhodesiense, strain EATRO-734) exhibited upregulated metabolic and detoxification processes [114].…”

Section: Drug Resistance Mechanismsmentioning

confidence: 99%

“…A study of trypanosomes obtained from suramin responsive and non-responsive HAT patients attempted to elucidate the underlying proteomic profiles of resistant trypanosomes [114]. The trypanosomes isolated from the non-responsive patients (T. b. rhodesiense, strain EATRO-734) exhibited upregulated metabolic and detoxification processes [114]. Furthermore, the mitochondrial proteome of the EATRO-734 strain was also demonstrated to be upregulated.…”

Section: Drug Resistance Mechanismsmentioning

confidence: 99%

“…Furthermore, the mitochondrial proteome of the EATRO-734 strain was also demonstrated to be upregulated. Inadequacies in the endosomal pathway are also implicated in suramin resistance [114]. Regarding DFMO, a single gene (TbAAT6) has been determined to encode the transporter of the drug, whereby the loss or knockdown of the gene results in drug resistance [115].…”

Section: Drug Resistance Mechanismsmentioning

confidence: 99%

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Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Jamabo,

Mahlalela,

Edkins

et al. 2023

IJMS

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Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite Trypanosoma brucei, and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed.

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Structure‐Activity Relationships, Tolerability and Efficacy of Microtubule‐Active 1,2,4‐Triazolo[1,5‐a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis**

et al. 2023

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Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT‐active compounds hold promise as antitrypanosomal agents. MT‐targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β‐tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure‐activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei‐infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24 h. Further, two once‐weekly doses at 10 mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS‐active TPDs may provide alternative treatments for human African trypanosomiasis.

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Physiological and proteomic profiles of Trypanosoma brucei rhodesiense parasite isolated from suramin responsive and non-responsive HAT patients in Busoga, Uganda

Cited by 4 publications

References 82 publications

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies

Structure‐Activity Relationships, Tolerability and Efficacy of Microtubule‐Active 1,2,4‐Triazolo[1,5‐a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis**

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