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    Retargeting azithromycin analogues to have dual-modality antimalarial activity

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    Author
    Burns, AL; Sleebs, BE; Siddiqui, G; De Paoli, AE; Anderson, D; Liffner, B; Harvey, R; Beeson, JG; Creek, DJ; Goodman, CD; ...
    Date
    2020-09-29
    Source Title
    BMC Biology
    Publisher
    BMC
    University of Melbourne Author/s
    Beeson, James; Sleebs, Brad
    Affiliation
    Medicine and Radiology
    Veterinary Biosciences
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Burns, A. L., Sleebs, B. E., Siddiqui, G., De Paoli, A. E., Anderson, D., Liffner, B., Harvey, R., Beeson, J. G., Creek, D. J., Goodman, C. D., McFadden, G. I. & Wilson, D. W. (2020). Retargeting azithromycin analogues to have dual-modality antimalarial activity. BMC BIOLOGY, 18 (1), https://doi.org/10.1186/s12915-020-00859-4.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252930
    DOI
    10.1186/s12915-020-00859-4
    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.

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