Retargeting azithromycin analogues to have dual-modality antimalarial activity

BMC Biology

James G. Beeson¹  Ghizal Siddiqui²  Darren J. Creek²  Amanda E. De Paoli²  Dovile Anderson²  Amy L. Burns³  Benjamin Liffner³  Richard Harvey³  Danny W. Wilson⁴  Geoffrey I. McFadden⁵  Christopher D. Goodman⁵  Brad E. Sleebs⁶ 

[1] Burnet Institute, 3004, Melbourne, Victoria, Australia;Department of Medicine, University of Melbourne, Melbourne, Australia;Central Clinical School and Department of Microbiology, Monash University, Melbourne, Australia;Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Melbourne, Victoria, Australia;Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, 5005, Adelaide, Australia;Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, 5005, Adelaide, Australia;Burnet Institute, 3004, Melbourne, Victoria, Australia;School of Biosciences, University of Melbourne, 3010, Melbourne, Victoria, Australia;Walter and Eliza Hall Institute of Medical Research, 3050, Melbourne, Victoria, Australia;Department of Medical Biology, University of Melbourne, 3050, Melbourne, Victoria, Australia;

关键词: Plasmodium;    Malaria;    Antimalarial;    Macrolide;   

DOI  :  10.1186/s12915-020-00859-4

来源: Springer

【 摘 要 】

BackgroundResistance 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.ResultsInvestigation 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.ConclusionWe 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.

【 授权许可】

CC BY