title: Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum.
abstract: BACKGROUND
  Malaria 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.
  
  
  RESULTS
  Here, 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.
  
  
  CONCLUSIONS
  Safe and effective macrolide antibiotics with dual modalities could be developed to combat malaria and reduce the parasite's options for resistance.
authors.affiliation: Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia. danny.wilson@adelaide.edu.au.|Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. danny.wilson@adelaide.edu.au.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. danny.wilson@adelaide.edu.au.|Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. danny.wilson@adelaide.edu.au.
authors.forename: Danny W
authors.initials: DW
authors.lastname: Wilson
authors.affiliation: Plant Cell Biology Research Centre, School of Biosciences, University of Melbourne, Parkville, Victoria, 3010, Australia. deang@unimelb.edu.au.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. sleebs@wehi.EDU.AU.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. sleebs@wehi.EDU.AU.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. weiss@burnet.edu.au.
authors.forename: Greta E
authors.initials: GE
authors.lastname: Weiss
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. nienkedejong88@gmail.com.
authors.forename: Nienke Wm
authors.initials: NW
authors.lastname: de Jong
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. angrisano@wehi.EDU.AU.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. angrisano@wehi.EDU.AU.|Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK. angrisano@wehi.EDU.AU.
authors.forename: Fiona
authors.initials: F
authors.lastname: Angrisano
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. langer@burnet.edu.au.
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. jake.baum@imperial.ac.uk.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. jake.baum@imperial.ac.uk.|Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK. jake.baum@imperial.ac.uk.
authors.forename: Jake
authors.initials: J
authors.lastname: Baum
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. crabb@burnet.edu.au.|Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. crabb@burnet.edu.au.|Department of Immunology, Monash University, Clayton, Victoria, 3800, Australia. crabb@burnet.edu.au.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. gilson@burnet.edu.au.|Department of Immunology, Monash University, Clayton, Victoria, 3800, Australia. gilson@burnet.edu.au.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: Plant Cell Biology Research Centre, School of Biosciences, University of Melbourne, Parkville, Victoria, 3010, Australia. fad1@mac.com.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. beeson@burnet.edu.au.|Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. beeson@burnet.edu.au.|Department of Microbiology, Monash University, Clayton, Victoria, 3168, Australia. beeson@burnet.edu.au.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000818:Animals; D000852:Anopheles; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D017963:Azithromycin / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D004917:Erythromycin / Q000737:chemistry / Q000494:pharmacology*; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology
chemical_list: D000962:Antimalarials; D004917:Erythromycin; D017963:Azithromycin