Decoding anti-leishmanial drug efficacy determinants.

Our first pre-print on BioRxiv!

Chemogenomic profiling of anti-leishmanial efficacy and resistance in the related kinetoplastid parasite Trypanosoma brucei

Selecting our T. brucei RNAi library in the anti-HAT drugs revolutionised our understanding of their mode of action and the ways the parasite can develop resistance. Unfortunately, an equivalent approach doesn’t yet exist in the related kinetoplastid parasite, Leishmania, which causes leishmaniasis, a devastating disease that’s endemic to a wide swathe of the tropics and sub-tropics.

However, the T. brucei and Leishmania genomes exhibit remarkable synteny, and these parasites share much in their biochemistry and cell biology (though their life styles are different – extra and intracellular, respectively). Therefore, we decided to select the T. brucei RNAi library in the anti-leishmanial drugs to see what insights we could gain into anti-leishmanial drug action and potential resistance mechanisms.

We identified 44 proteins, including T. brucei orthologues of the two known Leishmania drug transporters. The remaining 42 hits hadn’t previously been associated with anti-leishmanial drug action. Several of these were validated in T. brucei, highlighting the importance of a lysosomal transporter to paromomycin, and membrane trafficking and structure to amphotericin-B, as well as identifying a potential contributor to amphotericin-B/miltefosine cross-resistance.

This cohort of proteins represents a valuable resource for future study in Leishmania and has revealed some intriguing biology in T. brucei.