Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum

BMC Biology

Research Article

Brendan S Crabb¹  Christine Langer²  Nienke WM de Jong²  Greta E Weiss²  Paul R Gilson³  Christopher D Goodman⁴  Geoffrey I McFadden⁴  Danny W Wilson⁵  Brad E Sleebs⁶  Fiona Angrisano⁷  Jake Baum⁷  James G Beeson⁸ 

[1] Department of Medical Biology, University of Melbourne, 3050, Parkville, Victoria, Australia;Macfarlane Burnet Institute for Medical Research and Public Health, 3004, Melbourne, Victoria, Australia;Department of Immunology, Monash University, 3800, Clayton, Victoria, Australia;Macfarlane Burnet Institute for Medical Research and Public Health, 3004, Melbourne, Victoria, Australia;Macfarlane Burnet Institute for Medical Research and Public Health, 3004, Melbourne, Victoria, Australia;Department of Immunology, Monash University, 3800, Clayton, Victoria, Australia;Plant Cell Biology Research Centre, School of Biosciences, University of Melbourne, 3010, Parkville, Victoria, Australia;Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia;Walter and Eliza Hall Institute of Medical Research, 3050, Parkville, Victoria, Australia;Department of Medical Biology, University of Melbourne, 3050, Parkville, Victoria, Australia;Macfarlane Burnet Institute for Medical Research and Public Health, 3004, Melbourne, Victoria, Australia;Walter and Eliza Hall Institute of Medical Research, 3050, Parkville, Victoria, Australia;Department of Medical Biology, University of Melbourne, 3050, Parkville, Victoria, Australia;Walter and Eliza Hall Institute of Medical Research, 3050, Parkville, Victoria, Australia;Department of Medical Biology, University of Melbourne, 3050, Parkville, Victoria, Australia;Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ, London, UK;Walter and Eliza Hall Institute of Medical Research, 3050, Parkville, Victoria, Australia;Macfarlane Burnet Institute for Medical Research and Public Health, 3004, Melbourne, Victoria, Australia;Department of Microbiology, Monash University, 3168, Clayton, Victoria, Australia;

关键词: Plasmodium;    Merozoite;    Invasion;    Macrolide;    Dual modality;   

DOI  :  10.1186/s12915-015-0162-0

 received in 2015-01-26, accepted in 2015-06-30,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMalaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessible to inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarial agents act against host cell invasion.ResultsHere, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill human malaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of red blood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidence demonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent of its inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drug with multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasion inhibitors than parent compounds, offering promise for development of this novel antimalarial strategy.ConclusionsSafe and effective macrolide antibiotics with dual modalities could be developed to combat malaria and reduce the parasite’s options for resistance.

【 授权许可】

CC BY   
© Wilson et al. 2015