Amino acid transport and drug efficacy

Back in 2012, we published our study decoding the anti-T. brucei drug efficacy determinants – or parasite proteins critical to drug action, such as drug transporters and activators. This identified a slew of proteins that drive the action of the five anti-HAT drugs. More recently, we’ve been following up on a few of these proteins, leading to our 2015 paper on the role of two deubiquitinases in suramin action. In July, we published a paper in the FASEB Journal describing a pair of ornithine-transporting amino acid transporters (or AATs) that impact suramin and eflornithine efficacy.

AAT10.1 was identified in our original RNAi library screen. We confirmed that it’s loss led to reduced suramin efficacy, but remarkably we found AAT10.1 loss also increased eflornithine sensitivity. This led us to speculate that it might be transporting ornithine, as loss of ornithine-spermidine pathway enzymes has similar opposing effects on these drugs. Work by Juan Macedo while in Doris Rentsch’s lab confirmed this, and added to the complexity, identifying a second AAT not seen in the original screen. Intriguingly, AAT2.4’s ability to transport ornithine is dependent on exogenous histidine levels – when they’re high, ornithine can only be taken up by AAT10.1, probably explaining why we didn’t identify AAT2.4 in our original screen (histidine is very abundant in T. brucei culture media).

These results highlight how distant processes can influence drug action – neither transporter interacts with either drug, yet both can have a significant influence on drug efficacy. Finally, the impact of AAT10.1 loss on eflornithine action, highlights a possible means to potentiate the efficacy of this frontline anti-HAT drug – specific inhibition of AAT10.1 may enable the use of considerably lower doses of eflornithine. However, the high degree of conservation between AATs may preclude such a development.