Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate
Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate
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DOI：
10.1016/j.actatropica.2007.07.007
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发表时间：
2007-11-01
期刊：
影响因子：
2.7
通讯作者：
Brun, Reto
中科院分区：
文献类型：
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作者：
Maina, Naomi;Maina, Kagira Joseph;Brun, Reto
锥虫对三聚氰胺的抗性归因于通过P2核苷转运体对药物的摄取减少。本研究的目的是寻找来自南苏丹Ibba昏睡病患者的布氏冈比亚锥虫分离株的耐药性证据，这是一个高褪黑胂醇失败率的地区。18株冈比亚锥虫具有表型特征，仅有10株具有基因特征。在体外，所有分离株均对三聚氰胺、氧化三聚氰胺和咪纳苯敏感。感染小鼠用2.5 mg/kg体重的美拉胂醇治疗4天治愈，证实了分离株的敏感性。编码P2转运体的TbATI基因通过PCR扩增并测序。该序列与TbATI（敏感）参考几乎相同，除了一个点突变C1384T导致氨基酸从脯氨酸-462变为丝氨酸。未检测到所描述的TbATI（耐药）型突变。在冈比亚锥虫昏睡病疫区，由于治疗失败率高而不得不放弃使用美拉胂醇，没有发现耐药锥虫或TbATI（耐药）型P2转运体等位基因的证据。这些发现表明，除耐药性外，其他因素导致了美拉胂醇治疗失败。(c) 2007 Elsevier BX版权所有
Resistance of trypanosomes to melarsoprol is ascribed to reduced uptake of the drug via the P2 nucleoside transporter. The aim of this study was to look for evidence of drug resistance in Trypanosoma brucei gambiense isolates from sleeping sickness patients in Ibba, South Sudan, an area of high melarsoprol failure rate. Eighteen T. b. gambiense stocks were phenotypically and only 10 strains genotypically characterized. In vitro, all isolates were sensitive to melarsoprol, melarsen oxide, and diminazene. Infected mice were cured with a 4 day treatment of 2.5 mg/kg bwt melarsoprol, confirming that the isolates were sensitive. The gene that codes for the P2 transporter, TbATI, was amplified by PCR and sequenced. The sequences were almost identical to the TbATI(sensitive) reference, except for one point mutation, C1384T resulting in the amino acid change proline-462 to serine. None of the described TbATI(resistant)-type mutations were detected. In a T b. gambiense sleeping sickness focus where melarsoprol had to be abandoned due to the high incidence of treatment failures, no evidence for drug resistant trypanosomes or for TbATI(resistant)-type alleles of the P2 transporter could be found. These findings indicate that factors other than drug resistance contribute to melarsoprol treatment failures. (c) 2007 Elsevier BX All rights reserved.