Projects per year
Abstract
Background: 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 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.
Results: Investigation 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.
Conclusion: We 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.
Original language | English |
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Article number | 133 |
Number of pages | 23 |
Journal | BMC Biology |
Volume | 18 |
Issue number | 1 |
DOIs | |
Publication status | Published - 29 Sept 2020 |
Keywords
- Antimalarial
- Macrolide
- Malaria
- Plasmodium
Projects
- 1 Finished
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Enhancing anti-parasitic drug discovery with metabolomics
Creek, D. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/21
Project: Research
Equipment
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Monash Proteomics & Metabolomics Platform (MPMP)
Schittenhelm, R. (Other) & Steer, D. (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility