Table 4.

Anti-trypanosomal drugs, transporters, and drug resistance.

Drug name	Trypanosoma transporter	Mechanism of trypanocide resistance	Type of drug resistance	References
Nifurtimox	P2 aminopurine transporter which is encoded by TbAT1 gene	Loss of the P2 aminopurine transporter which is encoded by the gene TbAT1 Changes in TbAT1 through, deletions, chimeric rearrangement, and mutations	Resistance to nifurtimox	(145–148)
Suramin	Endocytic pathway invariant surface glycoprotein ISG75	Loss of function of the suramin receptor (ISG75) Also involves loss of function for lysosomal proteases (Cathepsin L), endosomal proteins, and a lysosome-based major facilitator superfamily (MFST)	Resistance to suramin	(145, 146, 148, 149)
Melarsoprol	P2-purine transporter	Resistance mechanisms for the MPA melarsoprol are similar to that of the diamidines due to similar motifs in the benzamidine moieties and melamine-phenyl group; therefore, “impairment in permeability to, or affinity of, the melamine grouping in the melarsen-resistant strain also prevents the uptake of the “amidine-type drugs”	Melarsoprol/pentamidine cross-resistance (MPXR)	(145, 146, 148, 150, 151)
Eflornithine	AAT6 (amino acid transporter 6) encoded by the gene TbAAT6	A single point mutation, e.g., deletions of the gene TbAAT6 are associated with significant drug resistance	Resistance to eflornithine	(145, 152–154)
Diamidine: Pentamidine (most used drug for early HAT)	Aquaglyceroporin 2 (TbAQP2) Additional pentamidine/arsenical transporters: high-affinity pentamidine transporter (HAPT1) and low-affinity pentamidine transporter (LAPT1), encoded by TbAQP2 and TbAQP3	Loss of the P2 aminopurine transporter encoded by the TbAT1 gene Deletions, mutations, and chimeric rearrangements with the adjacent TbAQP3 gene causes changes in TbAQP2	MPXR Selective resistance to pentamidine and high-level MPXR	(145, 146, 148, 151)
Diamidine: Diminazene (most used drug for early AAT)	TbAT1/P2	Loss of the P2 aminopurine transporter encoded by the gene TbAT1, also chimeric rearrangements, mutations, deletions with TbAQP3 gene that is adjacent causes changes in TbAQP2	Resistance to the veterinary diamidine diminazene, melarsoprol/pentamidine cross-resistance (MPXR)	(145, 146, 148, 150)