Retargeting azithromycin analogues to have dual-modality antimalarial activity
- Author(s)
- Burns, AL; Sleebs, BE; Siddiqui, G; De Paoli, AE; Anderson, D; Liffner, B; HARVEY, R; Beeson, JG; Creek, DJ; Goodman, CD; McFadden, GI; Wilson, DW;
- Details
- Publication Year 2020-09-29,Volume 18,Issue #1,Page 133
- Journal Title
- BMC Biology
- Publication Type
- Journal Article
- 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.
- Publisher
- BMC
- Research Division(s)
- Chemical Biology
- PubMed ID
- 32993629
- Publisher's Version
- https://doi.org/10.1186/s12915-020-00859-4
- Open Access at Publisher's Site
https://doi.org/10.1186/s12915-020-00859-4- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-10-02 02:01:47
Last Modified: 2020-10-02 02:09:30