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Abstract
Defining mode of action is vital for both developing new drugs and predicting potential resistance mechanisms. Sensitivity of African trypanosomes to pentamidine and melarsoprol is predominantly mediated by aquaglyceroporin 2 (TbAQP2), a channel associated with water/glycerol transport. TbAQP2 is expressed at the flagellar pocket membrane and chimerisation with TbAQP3 renders parasites resistant to both drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; that TbAQP2 mediates pentamidine translocation across the plasma membrane or via binding to TbAQP2, with subsequent endocytosis and presumably transport across the endosomal/lysosomal membrane, but as trafficking and regulation of TbAQPs is uncharacterised this remains unresolved. We demonstrate that TbAQP2 is organised as a high order complex, is ubiquitylated and is transported to the lysosome. Unexpectedly, mutation of potential ubiquitin conjugation sites, i.e. cytoplasmic-oriented lysine residues, reduced folding and tetramerization efficiency and triggered ER retention. Moreover, TbAQP2/TbAQP3 chimerisation, as observed in pentamidine-resistant parasites, also leads to impaired oligomerisation, mislocalisation and increased turnover. These data suggest that TbAQP2 stability is highly sensitive to mutation and that instability contributes towards the emergence of drug resistance.
Highlights
Human African trypanosomiasis (HAT) is a neglected tropical disease affecting sub-Saharan countries [1,2,3,4]
We find that the protein is highly sensitive to mutation, rendering the protein unstable, and rendering parasites
Several drugs are used to treat HAT; currently suramin and pentamidine are the drugs of choice for treatment of the haemolymphatic stage of T. brucei rhodesiense and T. brucei gambiense infections respectively, whereas melarsoprol, eflornithine or combined nifurtimox-eflornithine (NECT) therapy are recommended for the meningoencephalic stage [6,7], and more recently fexinidazole as second-line treatment for T. b. rhodesiense [8]
Summary
Human African trypanosomiasis (HAT) is a neglected tropical disease affecting sub-Saharan countries [1,2,3,4]. Several drugs are used to treat HAT; currently suramin and pentamidine are the drugs of choice for treatment of the haemolymphatic stage of T. brucei rhodesiense and T. brucei gambiense infections respectively, whereas melarsoprol, eflornithine or combined nifurtimox-eflornithine (NECT) therapy are recommended for the meningoencephalic stage [6,7], and more recently fexinidazole as second-line treatment for T. b. Fexinidazole [8] and acoziborole, recently completed clinical trials and opened a new front in HAT chemotherapy. Successful public health initiatives and active case-monitoring programs have all contributed to the anticipated elimination of gambiense HAT as a major public health problem in the coming decade [9]. Vigilance and understanding of drug mechanisms and possible resistance pathways remain essential to maintaining this situation, and rhodesiense HAT is unlikely to be eliminated as it is highly zoonotic [10]. Genome-wide RNAi screens identified a number of genes associated with pentamidine sensitivity that, together with evidence from melarsoprol-pentamidine cross-resistance (MPXR), identified aquaglyceroporin 2 as the primary determinant for druguptake [11,12], alongside lesser roles for the TbAT1/P2 aminopurine transporter and the low affinity pentamidine transporter LAPT1 [13]
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