Abstract
BackgroundResistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing ‘delayed-death’ activity against the parasite’s apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action.ResultsInvestigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on ‘quick-killing’ activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity.ConclusionWe show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.
Highlights
Resistance to front-line antimalarials is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed
Azithromycin analogues show improvement in quickkilling activity against P. falciparum We characterised the activity of 84 azithromycin analogues across the malaria parasites asexual blood-stage development in fine detail, including their activity against early ring stages
We tested for quick-killing activity using 44 hr in-cycle assays, wherein 10 μM of drug was added to early ring-stage D10PfPHG parasites within a few hours of invasion and parasite development quantified at late schizont stage with no exposure of invading merozoites to the drug
Summary
Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has been tested as monotherapy. Current control strategies include use of insecticide treated bednets and indoor residual spraying, which target mosquito transmission, chemoprophylaxis in high-risk groups, and artemisinin combination therapies (ACTs) to both cure patients and limit their transmission. Widespread use of these control measures has resulted in significant decreases in malaria mortality over the past two decades [1, 2]. New antimalarials with novel mechanisms of action that rapidly clear blood-stage parasites are urgently needed [8, 9]
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