Back to Search
Start Over
Retargeting azithromycin analogues to have dual-modality antimalarial activity
- Source :
- BMC Biology, Vol 18, Iss 1, Pp 1-23 (2020), BMC Biology
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
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.
- Subjects :
- Plasmodium
Physiology
Plasmodium vivax
Plasmodium falciparum
Antimalarial
Plant Science
Pharmacology
Azithromycin
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Antimalarials
Structural Biology
Chloroquine
parasitic diseases
medicine
Food vacuole
Malaria, Vivax
Plasmodium knowlesi
Artemisinin
Malaria, Falciparum
lcsh:QH301-705.5
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
0303 health sciences
Apicoplast
biology
030306 microbiology
Cell Biology
biology.organism_classification
Malaria
lcsh:Biology (General)
Macrolide
General Agricultural and Biological Sciences
Developmental Biology
Biotechnology
medicine.drug
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 17417007
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC Biology
- Accession number :
- edsair.doi.dedup.....9e6e7be1667e591ccacb4092988b2ef1