Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

January Weiner,Taco Kooij

doi:10.15698/mic2016.10.534

Abstract

In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

Highlights

The malaria parasite has adopted a highly complex life cycle involving a continuous switching between vertebrate hosts and anopheline mosquitoes
Using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs
We present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites

Summary

INTRODUCTION

The malaria parasite has adopted a highly complex life cycle involving a continuous switching between vertebrate hosts and anopheline mosquitoes. It is obvious that the development of the ideal anti-malarial drug will not be straightforward and will result in a compromise between the long list of desirable attributes and features In this light, it is important that ongoing functional studies of malaria parasite biology continue to highlight potential new drug targets that have important roles in the different life-cycle stages of the parasite and are conserved among all malaria parasite species but are absent from or have diverged significantly in humans, such that compounds acting on these important Plasmodium proteins may do so effectively as well as selectively. To further validate the potential of the eight newly identified drug targets, we have explored their phylogenetic relationships in detail

RESULTS AND DISCUSSION

Conclusions

MATERIALS AND METHODS