Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

Kasozi, Keneth Iceland; MacLeod, Ewan T.; Welburn, Susan C.

doi:10.3390/pathogens11101100

Cited by 10 publications

(2 citation statements)

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“…Trypanocide resistance in both humans ( Kasozi et al, 2022 ) and animals ( Wangwe et al, 2019 ; Kasozi et al, 2023 ) raises major public health risks following expression of cross-species resistance genes ( Kasozi et al, 2022 ; Okello et al, 2022 ). Animal African trypanocide resistance has previously been associated with poor farming practices, farmer treatments, underdosing and untrained personnel ( Ngumbi and Silayo, 2017 ; Kasozi et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Trypanocide usage in the cattle belt of southwestern Uganda

Kasozi,

MacLeod,

Sones

et al. 2023

Front. Microbiol.

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BackgroundSystematic infrastructure and regulatory weaknesses over many decades, in communities struggling with animal African trypanosomiasis (AAT) would be expected to create an environment that would promote drug misuse and risk development of drug resistance. Here, we explore rural community practices of livestock keepers, livestock extension officers and drug shop attendants to determine whether appropriate practice was being followed in administration of trypanocides and other drugs.MethodsA questionnaire-based survey was undertaken in southwestern Uganda in 2022 involving 451 farmers who kept cattle, sheep or goats and 79 “professionals” who were either livestock extension officers or drug shop attendants.ResultsRespondents reported using one or more type of trypanocidal drug on 80.1% of the 451 farms in the last 30 days. Diminazene aceturate was used on around three-quarters of farms, while isometamidium chloride was used on around one-fifth. Homidium bromide was used on less than 1% of farms. Cattle were significantly more likely to be treated with trypanocides than sheep or goats. On around two-thirds of farms, trypanocides were prepared and injected by farmers, with extension officers administering these drugs on most of the other third, especially on cattle farms. Almost all drugs were obtained from privately-owned drug shops. For treatment of AAT with trypanocides, prescription-only medicines were routinely used by farmers without professional supervision and in the absence of a definitive diagnosis. While a far greater proportion of professionals had a better education and had received training on the use of trypanocides than farmers, there was relatively little difference in their ability to use these drugs correctly. Farmers were more likely than professionals to use only DA to treat trypanosomiasis and were more likely to use antibiotics as well as trypanocidal drugs to treat the animal. Furthermore, they estimated, on average, that twice the recommended dose of either diminazene aceturate or isometamidium chloride was needed to treat a hypothetical 400 kg bovine. A minority of both farmers and professionals reported that they observed the recommended withdrawal times following injection of trypanocidal drugs and very few of either group knew the recommended withdrawal times for milk or meat. Only one in six farmers reported using the sanative pair (alternating use of diminazene aceturate and isometamidium chloride), to reduce the risk of drug resistant trypanosome strains emerging, while this approach was more widely used by professionals. Farmers reported using antibiotics more commonly than the professionals, especially in sheep and goats, raising concerns as to overuse and misuse of this critical class of drugs. In addition to using trypanocides, most farmers also reported using a topical veterinary pesticide for the control of ticks and tsetse. On average, farmers spent 12.2% of their income from livestock sales on trypanocides.ConclusionThis study highlights the complexity of issues involved in the fight against AAT using drug treatment. A multistakeholder campaign to increase awareness among farmers, drug shop attendants, and extension workers of the importance of adherence to recommended drug dosing, using the sanative pair and following recommended drug withdrawal guidance would promote best practice, reduce the risk of emergence of resistant strains of trypanosomes, and support enhanced food safety.

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Section: Introductionmentioning

confidence: 99%

Trypanocide usage in the cattle belt of southwestern Uganda

Kasozi,

MacLeod,

Sones

et al. 2023

Front. Microbiol.

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“…Trypanosoma brucei is a parasitic protozoan that belongs to a group of very early divergent eukaryotes. T. brucei causes a fatal disease in humans known as African Sleeping Sickness and a similar disease in livestock, called Wasting Syndrome or Nagana (Sternberg and Maclean, 2010;Kasozi et al, 2022). One of the several unique characteristics of T. brucei is that it possesses a single mitochondrion per cell that is elongated along the cell body (Zikova 2022; Chaudhuri et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Distinct structural motifs are necessary for targeting and import of Tim17 inTrypanosoma bruceimitochondrion

Darden,

Donkor,

Korolkova

et al. 2023

Preprint

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Nuclear-encoded mitochondrial proteins are correctly translocated to their proper sub-mitochondrial destination using location specific mitochondrial targeting signals (MTSs) and via multi-protein import machineries (translocases) in the outer and inner mitochondrial membranes (TOM and TIMs, respectively). However, MTSs of multi-pass Tims are less defined. Here we report the characterization of the MTSs of Trypanosoma brucei Tim17 (TbTim17), an essential component of the most divergent TIM complex. TbTim17 possesses a characteristic secondary structure including four predicted transmembrane (TM) domains in the center with hydrophilic N- and C- termini. After examining mitochondrial localization of various deletion and site-directed mutants of TbTim17 in T. brucei using subcellular fractionation and confocal microscopy we located at least two internal signals, 1) within TM1 (31-50 AAs) and 2) TM4 + Loop 3 (120-136 AAs). Both signals are required for proper targeting and integration of TbTim17 in the membrane. Furthermore, a positively charged residue (K122) is critical for mitochondrial localization of TbTim17. This is the first report of characterizing the internal mitochondrial targeting signals (ITS) for a multipass inner membrane protein in a divergent eukaryote, like T. brucei.

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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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Systematic Review and Meta-Analysis on Human African Trypanocide Resistance

Cited by 10 publications

References 74 publications

Trypanocide usage in the cattle belt of southwestern Uganda

Trypanocide usage in the cattle belt of southwestern Uganda

Distinct structural motifs are necessary for targeting and import of Tim17 inTrypanosoma bruceimitochondrion

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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