General Information of the Disease (ID: DIS00174)
Name
African trypanosomiasis
ICD
ICD-11: 1F51
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
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Melarsoprol
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Aquaporin 2 (AQP2) [1]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Down-regulation
Resistant Drug Melarsoprol
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model African trypanosomiasis strain .
Mechanism Description The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.
Key Molecule: Aquaporin 2/3 (AQP2/3) [1]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Up-regulation
Resistant Drug Melarsoprol
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model African trypanosomiasis strain .
Mechanism Description The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.
Pentamidine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: High-affinity pentamidine transporter (HAPT1) [2]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Down-regulation
Resistant Drug Pentamidine
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Trypanosoma brucei strain 5691
Mechanism Description While a high level of resistance to diminazene was observed, the resistance factor for pentamidine and the melaminophenyl arsenicals were only two to threefold, significantly less than the arsenical-pentamidine cross-resistant strains generated in the laboratory. Thus, it was clear that at least one additional transporter must contribute to the cross-resistance phenotype. The prime candidate was the high-affinity pentamidine transporter (HAPT1), an activity recorded in bloodstream-form T. brucei using low nanomolar concentrations of [3H]-pentamidine. Melarsoprol also appears to be a substrate for HAPT1 and selection for increased resistance to pentamidine or melarsoprol in Tbat1 null cells led to specific loss of HAPT1 activity.
Key Molecule: Aquaporin 2 (AQP2) [1]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Down-regulation
Resistant Drug Pentamidine
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model African trypanosomiasis strain .
Mechanism Description The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.
Key Molecule: Aquaporin 2/3 (AQP2/3) [1]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Up-regulation
Resistant Drug Pentamidine
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model African trypanosomiasis strain .
Mechanism Description The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: NADH dehydrogenase [ubiquinone] flavoprotein 1 (TbAT1) [2]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Down-regulation
Resistant Drug Pentamidine
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Trypanosoma brucei strain 5691
Mechanism Description Reduced uptake and cross-resistance were apparently explained by the findings that melamine-based arsenicals and diamidines are imported into trypanosomes by the same transporter, and that this transporter is defective in drug-resistant cells. The transporter was called P2 (purine transporter 2) as its physiological substrates are adenine and adenosine, both of which compete with melarsoprol for uptake and can protect trypanosomes from melarsoprol-induced lysis.
Investigative Drug(s)
1 drug(s) in total
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Melamine-based arsenicals
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: NADH dehydrogenase [ubiquinone] flavoprotein 1 (TbAT1) [2]
Resistant Disease African trypanosomiasis [ICD-11: 1F51.0]
Molecule Alteration Expression
Down-regulation
Resistant Drug Melamine-based arsenicals
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Trypanosoma brucei strain 5691
Mechanism Description Reduced uptake and cross-resistance were apparently explained by the findings that melamine-based arsenicals and diamidines are imported into trypanosomes by the same transporter, and that this transporter is defective in drug-resistant cells. The transporter was called P2 (purine transporter 2) as its physiological substrates are adenine and adenosine, both of which compete with melarsoprol for uptake and can protect trypanosomes from melarsoprol-induced lysis.
References
Ref 1 Melarsoprol Resistance in African Trypanosomiasis .Trends Parasitol. 2018 Jun;34(6):481-492. doi: 10.1016/j.pt.2018.04.002. Epub 2018 Apr 25. 10.1016/j.pt.2018.04.002
Ref 2 Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story .Trends Parasitol. 2013 Mar;29(3):110-8. doi: 10.1016/j.pt.2012.12.005. Epub 2013 Jan 30. 10.1016/j.pt.2012.12.005

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