The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; ORCID: http://orcid.org/0000-0001-5134-0329.
The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; ORCID: http://orcid.org/0000-0001-5173-9284.
Trends Parasitol. 2018 Jun;34(6):481-492. doi: 10.1016/j.pt.2018.04.002. Epub 2018 Apr 25.
Arsenicals were introduced as monotherapies for the treatment of human African trypanosomiasis, or sleeping sickness, over 100 years ago. Toxicity has always been an issue but these drugs have proven to be both effective and quite durable. Unfortunately, melarsoprol-resistant parasites emerged as early as the 1970s and were widespread by the late 1990s. Resistance was due to mutations affecting an aquaglyceroporin (AQP2), a parasite solute and drug transporter. This is the only example of widespread drug resistance in trypanosomiasis patients for which the genetic basis is known. This link between melarsoprol and AQP2 illustrates how a drug transporter can improve drug selectivity but, at the same time, highlights the risk of resistance when the drug uptake mechanism is dispensable for parasite viability and virulence.
100 多年前，砷剂被作为单一疗法引入治疗非洲人类锥虫病（昏睡病）。毒性一直是个问题，但这些药物已被证明既有效又耐用。不幸的是，早在 20 世纪 70 年代就出现了耐梅拉胂醇的寄生虫，到 20 世纪 90 年代末已广泛传播。耐药性是由于影响水甘油通道蛋白（AQP2）的突变引起的，AQP2 是寄生虫溶质和药物转运体。这是唯一已知遗传基础的广泛耐药性的锥虫病患者的例子。梅拉胂醇与 AQP2 之间的这种联系说明了药物转运体如何提高药物选择性，但同时也突出了在药物摄取机制对寄生虫生存力和毒力并非必不可少时，耐药性的风险。
