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Targeting malaria parasites with novel derivatives of azithromycin

ABSTRACT: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the apicoplast, and ‘quick-killing’ that kills rapidly across the entire blood stage development. Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Lead analogues had limited activity against the related parasite Toxoplasma gondii and were >5-fold more selective against malaria than human cells. Quick-killing analogues maintained activity throughout the blood stage lifecycle including ring stages of P. falciparum parasites (<12 hrs treatment). Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Metabolomic profiling of parasites subjected to the lead analogue revealed a similar profile to chloroquine treatment, suggesting that the food-vacuole is a likely target of this drugs activity. The azithromycin analogues characterised in this study expanded the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.

ORGANISM(S): Plasmodium Falciparum

TISSUE(S): Blood

DISEASE(S): Malaria

SUBMITTER: Ghizal Siddiqui

PROVIDER: ST002309 | MetabolomicsWorkbench | Tue Oct 04 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium parasites that cause malaria are urgently needed. Here, we show that azithromycin—a clinically used macrolide antibiotic that targets the bacterium-like ribosome of the malaria parasites apicoplast organelle and causes a slow-killing ‘delayed death’ phenotype—can also rapidly kill parasites throughout the asexual blood-stages of the lifecycle via a ‘quick-killing’ mechanism of action. Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency that is directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin for in vitro treatment windows less than 48 hours. Analogues were also effective against the zoonotic malaria parasite P. knowlesi, and against both multi-drug and artemisinin resistant P. falciparum lines. Metabolomic profiles of azithromycin analogue treated parasites were similar to those of chloroquine treated parasites, suggesting that the quick-killing mechanism of action may in part be localised to the parasite food vacuole. However, metabolomic signatures associated with mitochondrial disruption were also present. In addition, unlike 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, which suggests that apicoplast-targeting, delayed-death activity can either be preserved or removed independently of quick-killing. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Therefore, 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.

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Targeting malaria parasites with novel derivatives of azithromycin

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