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Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense.

ABSTRACT: Isometamidium Chloride (ISM) is one of the principal drugs used to counteract Trypanosoma congolense infection in livestock, both as a prophylactic as well as a curative treatment. However, numerous cases of ISM resistance have been reported in different African regions, representing a significant constraint in the battle against Animal African Trypanosomiasis. In order to identify genetic signatures associated with ISM resistance in T. congolense, the sensitive strain MSOROM7 was selected for induction of ISM resistance in a murine host. Administered ISM concentrations in immune-suppressed mice were gradually increased from 0.001 mg/kg to 1 mg/kg, the maximal dose used in livestock. As a result, three independent MSOROM7 lines acquired full resistance to this concentration after five months of induction, and retained this full resistant phenotype following a six months period without drug pressure. In contrast, parasites did not acquire ISM resistance in immune-competent animals, even after more than two years under ISM pressure, suggesting that the development of full ISM resistance is strongly enhanced when the host immune response is compromised. Genomic analyses comparing the ISM resistant lines with the parental sensitive line identified shifts in read depth at heterozygous loci in genes coding for different transporters and transmembrane products, and several of these shifts were also found within natural ISM resistant isolates. These findings suggested that the transport and accumulation of ISM inside the resistant parasites may be modified, which was confirmed by flow cytometry and ex vivo ISM uptake assays that showed a decrease in the accumulation of ISM in the resistant parasites.

SUBMITTER: Tihon E

PROVIDER: S-EPMC5645165 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense.

Tihon Eliane E Imamura Hideo H Van den Broeck Frederik F Vermeiren Lieve L Dujardin Jean-Claude JC Van Den Abbeele Jan J

International journal for parasitology. Drugs and drug resistance 20171006 3

Isometamidium Chloride (ISM) is one of the principal drugs used to counteract Trypanosoma congolense infection in livestock, both as a prophylactic as well as a curative treatment. However, numerous cases of ISM resistance have been reported in different African regions, representing a significant constraint in the battle against Animal African Trypanosomiasis. In order to identify genetic signatures associated with ISM resistance in T. congolense, the sensitive strain MSOROM7 was selected for i ...[more]

PMID: 29032180

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Project description:BACKGROUND: Because of the development of resistance in trypanosomes to trypanocidal drugs, the livelihood of millions of livestock keepers in sub-Saharan Africa is threatened now more than ever. The existing compounds have become virtually useless and pharmaceutical companies are not keen on investing in the development of new trypanocides. We may have found a breakthrough in the treatment of resistant trypanosomal infections, through the combination of the trypanocide isometamidium chloride (ISM) with two affordable veterinary antibiotics. METHODOLOGY/PRINCIPAL FINDINGS: In a first experiment, groups of mice were inoculated with Trypanosoma congolense strains resistant to ISM and either left untreated or treated with (i) tetracycline, (ii) ISM or (iii) the combination of the antibiotic and the trypanocide. Survival analysis showed that there was a significant effect of treatment and resistance to treatment on the survival time. The groups treated with ISM (with or without antibiotic) survived significantly longer than the groups that were not treated with ISM (P<0.01). The group treated with the combination trypanocide/antibiotic survived significantly longer than the group treated with ISM (P<0.01). In a second experiment, groups of cattle were inoculated with the same resistant trypanosome strain and treated with (i) ISM, (ii) ISM associated with oxytetracycline or (iii) ISM associated with enrofloxacine. All animals treated with ISM became parasitaemic. In the groups treated with ISM-oxytetracycline and ISM-enrofloxacine, 50% of the animals were cured. Animals from the groups treated with a combination trypanocide/antibiotic presented a significantly longer prepatent period than animals treated with ISM (p<0.001). The impact of the disease on the haematocrit was low in all ISM treated groups. Yet, it was lower in the groups treated with the combination trypanocide/antibiotic (p<0.01). CONCLUSIONS/SIGNIFICANCE: After optimization of the administration protocol, this new therapeutic combination could constitute a promising treatment for livestock infected with drug resistant T. congolense.

Dataset Information

Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense.

Publications

Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense.

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