Genomic Analysis of Isometamidium Chloride Resistance in Trypanosoma Congolense

Overview

Journal Int J Parasitol Drugs Drug Resist

Publisher Elsevier

Specialty Parasitology

Date 2017 Oct 17

PMID 29032180

Citations 20

Authors

Eliane Tihon

Hideo Imamura

Frederik Van den Broeck

Lieve Vermeiren

Jean-Claude Dujardin

Jan Van Den Abbeele

Affiliations

Soon will be listed here.

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.

Citing Articles

Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities.

Chirwa K, Francisco K, Dube P, Park H, Legoabe L, Teixeira T ChemMedChem. 2024; 19(9):e202300667.

PMID: 38326914 PMC: 11076157. DOI: 10.1002/cmdc.202300667.

Effects of Synthetic Ligustrazine-Based Chalcone Derivatives on and spp. Promastigotes.

Alkhaldi A Molecules. 2023; 28(12).

PMID: 37375205 PMC: 10300702. DOI: 10.3390/molecules28124652.

Trypanosoma Congolense Resistant to Trypanocidal Drugs Homidium and Diminazene and their Molecular Characterization in Lambwe, Kenya.

Okello I, Mafie E, Nzalawahe J, Eastwood G, Mboera L, Hakizimana J Acta Parasitol. 2022; 68(1):130-144.

PMID: 36441294 DOI: 10.1007/s11686-022-00640-3.

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania.

Cuypers B, Meysman P, Erb I, Bittremieux W, Valkenborg D, Baggerman G PLoS Pathog. 2022; 18(9):e1010848.

PMID: 36149920 PMC: 9534393. DOI: 10.1371/journal.ppat.1010848.

Investigation on Prevalence of Canine Trypanosomiasis in the Conservation Areas of Bwindi-Mgahinga and Queen Elizabeth in Western Uganda.

Ochieng J, Bachs M, Nsubuga A, Rwego I, Kisakye J, Riba L J Parasitol Res. 2022; 2022:2606871.

PMID: 36124129 PMC: 9482531. DOI: 10.1155/2022/2606871.

References

Delespaux V, Dinka H, Masumu J, Van Den Bossche P, Geerts S . Five-fold increase in Trypanosoma congolense isolates resistant to diminazene aceturate over a seven-year period in Eastern Zambia. Drug Resist Updat. 2008; 11(6):205-9. DOI: 10.1016/j.drup.2008.10.002. View

Peacock L, Ferris V, Sharma R, Sunter J, Bailey M, Carrington M . Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly. Proc Natl Acad Sci U S A. 2011; 108(9):3671-6. PMC: 3048101. DOI: 10.1073/pnas.1019423108. View

Munday J, Settimo L, de Koning H . Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei. Front Pharmacol. 2015; 6:32. PMC: 4356943. DOI: 10.3389/fphar.2015.00032. View

Neupert W . Protein import into mitochondria. Annu Rev Biochem. 1997; 66:863-917. DOI: 10.1146/annurev.biochem.66.1.863. View

Matovu E, Stewart M, Geiser F, Brun R, Maser P, Wallace L . Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryot Cell. 2003; 2(5):1003-8. PMC: 219364. DOI: 10.1128/EC.2.5.1003-1008.2003. View

Kaminsky R, Schmid C, Lun Z . Susceptibility of dyskinetoplastic Trypanosoma evansi and T. equiperdum to isometamidium chloride. Parasitol Res. 1997; 83(8):816-8. DOI: 10.1007/s004360050346. View

Eze A, Gould M, Munday J, Tagoe D, Stelmanis V, Schnaufer A . Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase. PLoS Negl Trop Dis. 2016; 10(8):e0004791. PMC: 4982688. DOI: 10.1371/journal.pntd.0004791. View

Gould M, Schnaufer A . Independence from Kinetoplast DNA maintenance and expression is associated with multidrug resistance in Trypanosoma brucei in vitro. Antimicrob Agents Chemother. 2014; 58(5):2925-8. PMC: 3993240. DOI: 10.1128/AAC.00122-14. View

Pinder M, Authie E . The appearance of isometamidium resistant Trypanosoma congolense in West Africa. Acta Trop. 1984; 41(3):247-52. View

10.

Yerushalmi H, Lebendiker M, Schuldiner S . EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents. J Biol Chem. 1995; 270(12):6856-63. DOI: 10.1074/jbc.270.12.6856. View

11.

Brun R, Lun Z . Drug sensitivity of Chinese Trypanosoma evansi and Trypanosoma equiperdum isolates. Vet Parasitol. 1994; 52(1-2):37-46. DOI: 10.1016/0304-4017(94)90033-7. View

12.

Downing T, Imamura H, Decuypere S, Clark T, Coombs G, Cotton J . Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. Genome Res. 2011; 21(12):2143-56. PMC: 3227103. DOI: 10.1101/gr.123430.111. View

13.

Liu B, Liu Y, Motyka S, Agbo E, Englund P . Fellowship of the rings: the replication of kinetoplast DNA. Trends Parasitol. 2005; 21(8):363-9. DOI: 10.1016/j.pt.2005.06.008. View

14.

Moti Y, De Deken R, Thys E, Van Den Abbeele J, Duchateau L, Delespaux V . PCR and microsatellite analysis of diminazene aceturate resistance of bovine trypanosomes correlated to knowledge, attitude and practice of livestock keepers in South-Western Ethiopia. Acta Trop. 2015; 146:45-52. DOI: 10.1016/j.actatropica.2015.02.015. View

15.

Tihon E, Imamura H, Dujardin J, Van Den Abbeele J, Van den Broeck F . Discovery and genomic analyses of hybridization between divergent lineages of Trypanosoma congolense, causative agent of Animal African Trypanosomiasis. Mol Ecol. 2017; 26(23):6524-6538. DOI: 10.1111/mec.14271. View

16.

Sutherland I, Mounsey A, Holmes P . Transport of isometamidium (Samorin) by drug-resistant and drug-sensitive Trypanosoma congolense. Parasitology. 1992; 104 ( Pt 3):461-7. DOI: 10.1017/s0031182000063721. View

17.

Chowdhury A, Bakshi R, Wang J, Yildirir G, Liu B, Pappas-Brown V . The killing of African trypanosomes by ethidium bromide. PLoS Pathog. 2010; 6(12):e1001226. PMC: 3002999. DOI: 10.1371/journal.ppat.1001226. View

18.

Osman A, JENNINGS F, Holmes P . The rapid development of drug-resistance by Trypanosoma evansi in immunosuppressed mice. Acta Trop. 1992; 50(3):249-57. DOI: 10.1016/0001-706x(92)90081-8. View

19.

Daniels J, Gull K, Wickstead B . Cell biology of the trypanosome genome. Microbiol Mol Biol Rev. 2010; 74(4):552-69. PMC: 3008170. DOI: 10.1128/MMBR.00024-10. View

20.

Gibson W, Peacock L, Ferris V, Williams K, Bailey M . The use of yellow fluorescent hybrids to indicate mating in Trypanosoma brucei. Parasit Vectors. 2008; 1(1):4. PMC: 2276490. DOI: 10.1186/1756-3305-1-4. View