Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum.

Danny W Wilson,Fiona Angrisano,Nienke Wm De Jong,Christine Langer,Geoffrey I Mcfadden,Brad E Sleebs,Jake Baum,James G Beeson,Paul R Gilson,Christopher D Goodman,Greta E Weiss,Brendan S Crabb

doi:10.1186/s12915-015-0162-0

Abstract

BackgroundMalaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessible to inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarial agents act against host cell invasion.ResultsHere, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill human malaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of red blood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidence demonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent of its inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drug with multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasion inhibitors than parent compounds, offering promise for development of this novel antimalarial strategy.ConclusionsSafe and effective macrolide antibiotics with dual modalities could be developed to combat malaria and reduce the parasite’s options for resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0162-0) contains supplementary material, which is available to authorized users.

Highlights

Malaria invasion of red blood cells involves multiple parasite-specific targets that are accessible to inhibitory compounds, making it an attractive target for antimalarial development
Azithromycin inhibits merozoite invasion Application of the merozoite purification method of Boyle et al [18] identified the macrolide antibiotic azithromycin as a candidate inhibitor of P. falciparum asexual blood-stage merozoite invasion of the host erythrocyte
Initial screens indicated that the invasion inhibitory IC50 differed between azithromycin prepared in ethanol (10 μM) or dimethyl sulfoxide (DMSO) (38 μM), suggesting that choice of vehicle can impact azithromycin potency in vitro

Summary

Introduction

Malaria invasion of red blood cells involves multiple parasite-specific targets that are accessible to inhibitory compounds, making it an attractive target for antimalarial development. Current disease control measures rely on reducing exposure to the mosquito vector or treatment of clinical malaria cases with antimalarial drugs that target the disease causing blood-stage trophozoite; most of these act against the parasite’s food vacuole or interfere with pyrimidine synthesis of maturing trophozoites [2,3,4,5,6]. Invasion of blood-stage merozoites into host cells has been proposed as a potential target for antimalarial chemotherapy [11,12,13,14]. Inhibition of merozoite invasion into the erythrocyte would lead to instant disruption of the parasite lifecycle and prevent sequestration, dormancy and commitment to the mosquito-transmissible gametocyte stage, which have been reported to occur after drug treatment with current first-line antimalarials [15,16,17]. Application of antimalarial drugs that target invasion has the potential to result in quicker resolution of clinical disease if used in combination with antimalarials that act at other developmental stages

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