Characterization of Two Malaria Parasite Organelle Translation Elongation Factor G Proteins: The Likely Targets of the Anti-Malarial Fusidic Acid

Russell A Johnson,Geoffrey I Mcfadden,Christopher D Goodman,Gordon Langsley

doi:10.1371/journal.pone.0020633

Abstract

Malaria parasites harbour two organelles with bacteria-like metabolic processes that are the targets of many anti-bacterial drugs. One such drug is fusidic acid, which inhibits the translation component elongation factor G. The response of P. falciparum to fusidic acid was characterised using extended SYBR-Green based drug trials. This revealed that fusidic acid kills in vitro cultured P. falciparum parasites by immediately blocking parasite development. Two bacterial-type protein translation elongation factor G genes are identified as likely targets of fusidic acid. Sequence analysis suggests that these proteins function in the mitochondria and apicoplast and both should be sensitive to fusidic acid. Microscopic examination of protein-reporter fusions confirm the prediction that one elongation factor G is a component of parasite mitochondria whereas the second is a component of the relict plastid or apicoplast. The presence of two putative targets for a single inhibitory compound emphasizes the potential of elongation factor G as a drug target in malaria.

Highlights

Numerous anti-bacterials are effective anti-malarials and are a part of current malaria management programs
With a view to further defining the likely target of fusidic acid in malaria parasites, we explore whether either or both of these organellar translation systems utilize elongation factor G (EF-G)
This contrasts with other translation-blocking antibacterials, such as azithromycin, clindamycin and tetracycline, which exhibit delayed death and have dramatically lower IC50 values at 96 hours compared to 48 hours (Fig. 1A, [15,17])

Summary

Introduction

Numerous anti-bacterials are effective anti-malarials and are a part of current malaria management programs. Doxycycline is widely prescribed for malaria chemoprophylaxis [1] and clindamycin and doxycycline are recommended for use in ACT therapy in the case of initial treatment failure [2]. Antibacterials typically work by blocking vital prokaryotic processes such as DNA replication, RNA transcription, protein translation, or peptidoglycan wall synthesis. The key to the success of antibacterials is that they target the fundamental differences between these processes in bacteria and the equivalent processes in humans and other eukaryotes. How anti-bacterials kill eukaryotic malaria parasites is not well understood. Two malaria parasite organelles derived from endosymbiotic bacteria, the mitochondrion and the relict plastid (or apicoplast), are the likely targets of these compounds

Methods

Results

Conclusion