2001
DOI: 10.1016/s0166-6851(01)00332-2
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Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy

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Cited by 91 publications
(114 citation statements)
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“…Nonetheless, the two-to threefold resistance to melaminophenyl arsenicals observed for this null mutant may still be clinically significant and is consistent with the absence of pronounced arsenical resistance in clinical isolates from melarsoprol-refractory patients (38). Another study of field isolates from distinct parts of Africa (37) revealed that many of the TbAT1 genes isolated from patients with relapsing infections after melarsoprol treatment exhibited the same set of nine mutations and that one relapse isolate was missing the TbAT1 gene altogether, again implicating this gene in drug resistance. It is difficult to fathom how a drug-resistant allele with so many of the same polymorphisms could have arisen independently on multiple occasions.…”
Section: Alterations In Parasite Purine Permeases Leading To Drug Ressupporting
confidence: 72%
“…Nonetheless, the two-to threefold resistance to melaminophenyl arsenicals observed for this null mutant may still be clinically significant and is consistent with the absence of pronounced arsenical resistance in clinical isolates from melarsoprol-refractory patients (38). Another study of field isolates from distinct parts of Africa (37) revealed that many of the TbAT1 genes isolated from patients with relapsing infections after melarsoprol treatment exhibited the same set of nine mutations and that one relapse isolate was missing the TbAT1 gene altogether, again implicating this gene in drug resistance. It is difficult to fathom how a drug-resistant allele with so many of the same polymorphisms could have arisen independently on multiple occasions.…”
Section: Alterations In Parasite Purine Permeases Leading To Drug Ressupporting
confidence: 72%
“…AT1 has been found to be mutated, deleted, or down-regulated in melarsoprol-resistant trypanosomes (10,42) but AT1 knockout generated cells with only a twofold increased resistance to both melarsoprol and pentamidine (14), and there is evidence for resistance that is independent of AT1 disruption (43,44). Our results now show that AQP2, when defective, could explain cases of innate MPXR and/or acquired MPXR of clinical relevance.…”
Section: Discussionmentioning
confidence: 58%
“…However, all drugs currently registered for use carry significant problems related to administration, toxicity, increasing incidence of treatment failure, and in the case of animal trypanosomiasis, drug resistance (1). Previous work has shown that defects in the P2 aminopurine transporter, encoded by the TbAT1 gene (the same gene in Trypanosoma equiperdum is referred to as TeAT1 [Trypanosoma equiperdum AT1] in this article), are linked to drug resistance in Trypanosoma brucei brucei (11,21), Trypanosoma brucei gambiense (22), and Trypanosoma brucei rhodesiense (28), as well as in Trypanosoma evansi (24,32) and T. equiperdum (3), very close phylogenetic relatives of T. brucei (27). The P2 transporter has been shown to be capable of carrying both melaminophenyl arsenical (11) and diamidine (10,14,15,18) classes of drug into African trypanosomes in the T. brucei group.…”
mentioning
confidence: 99%