Format

Send to

Choose Destination
BMC Biol. 2015 Jul 18;13:52. doi: 10.1186/s12915-015-0162-0.

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

Wilson DW1,2,3,4, Goodman CD5, Sleebs BE6,7, Weiss GE8, de Jong NW9, Angrisano F10,11,12, Langer C13, Baum J14,15,16, Crabb BS17,18,19, Gilson PR20,21, McFadden GI22, Beeson JG23,24,25.

Author information

1
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia. danny.wilson@adelaide.edu.au.
2
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. danny.wilson@adelaide.edu.au.
3
Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. danny.wilson@adelaide.edu.au.
4
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. danny.wilson@adelaide.edu.au.
5
Plant Cell Biology Research Centre, School of Biosciences, University of Melbourne, Parkville, Victoria, 3010, Australia. deang@unimelb.edu.au.
6
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. sleebs@wehi.EDU.AU.
7
Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. sleebs@wehi.EDU.AU.
8
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. weiss@burnet.edu.au.
9
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. nienkedejong88@gmail.com.
10
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. angrisano@wehi.EDU.AU.
11
Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. angrisano@wehi.EDU.AU.
12
Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK. angrisano@wehi.EDU.AU.
13
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. langer@burnet.edu.au.
14
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. jake.baum@imperial.ac.uk.
15
Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. jake.baum@imperial.ac.uk.
16
Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK. jake.baum@imperial.ac.uk.
17
Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3050, Australia. crabb@burnet.edu.au.
18
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. crabb@burnet.edu.au.
19
Department of Immunology, Monash University, Clayton, Victoria, 3800, Australia. crabb@burnet.edu.au.
20
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. gilson@burnet.edu.au.
21
Department of Immunology, Monash University, Clayton, Victoria, 3800, Australia. gilson@burnet.edu.au.
22
Plant Cell Biology Research Centre, School of Biosciences, University of Melbourne, Parkville, Victoria, 3010, Australia. fad1@mac.com.
23
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia. beeson@burnet.edu.au.
24
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, 3004, Australia. beeson@burnet.edu.au.
25
Department of Microbiology, Monash University, Clayton, Victoria, 3168, Australia. beeson@burnet.edu.au.

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.

PMID:
26187647
PMCID:
PMC4506589
DOI:
10.1186/s12915-015-0162-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center