Targeting malaria parasites with novel derivatives of azithromycin

Amy L. Burns; Amy L. Burns; Brad E. Sleebs; Brad E. Sleebs; Maria Gancheva; Kimberley T. McLean; Ghizal Siddiqui; Henrietta Venter; James G. Beeson; James G. Beeson; James G. Beeson; James G. Beeson; Ryan O’Handley; Ryan O’Handley; Darren J. Creek; Shutao Ma; Sonja Frölich; Christopher D. Goodman; Geoffrey I. McFadden; Danny W. Wilson; Danny W. Wilson; Danny W. Wilson

doi:10.3389/fcimb.2022.1063407

Frontiers in Cellular and Infection Microbiology (Nov 2022)

Targeting malaria parasites with novel derivatives of azithromycin

Amy L. Burns,
Amy L. Burns,
Brad E. Sleebs,
Brad E. Sleebs,
Maria Gancheva,
Kimberley T. McLean,
Ghizal Siddiqui,
Henrietta Venter,
James G. Beeson,
James G. Beeson,
James G. Beeson,
James G. Beeson,
Ryan O’Handley,
Ryan O’Handley,
Darren J. Creek,
Shutao Ma,
Sonja Frölich,
Christopher D. Goodman,
Geoffrey I. McFadden,
Danny W. Wilson,
Danny W. Wilson,
Danny W. Wilson

Affiliations

Amy L. Burns: Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia
Amy L. Burns: School of Science and Technology, the University of New England, Armidale, NSW, Australia
Brad E. Sleebs: ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Brad E. Sleebs: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Maria Gancheva: Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia
Kimberley T. McLean: Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia
Ghizal Siddiqui: Drug Delivery Disposition and Dynamics, Monash University, Parkville, VIC, Australia
Henrietta Venter: Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
James G. Beeson: Healthy Mothers, Healthy Babies Program, Burnet Institute, Melbourne, VIC, Australia
James G. Beeson: Department of Medicine, University of Melbourne, Parkville, VIC, Australia
James G. Beeson: Central Clinical School, Monash University, Melbourne, Vic, Australia
James G. Beeson: 0Department of Microbiology, Monash University, Melbourne, Vic, Australia
Ryan O’Handley: 1School of Animal and Veterinary Science, University of Adelaide, Adelaide, SA, Australia
Ryan O’Handley: 2Australian Centre for Antimicrobial Resistance Ecology, The University of Adelaide, Adelaide, SA, Australia
Darren J. Creek: Drug Delivery Disposition and Dynamics, Monash University, Parkville, VIC, Australia
Shutao Ma: 3Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, China
Sonja Frölich: Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia
Christopher D. Goodman: 4School of BioSciences, University of Melbourne, Parkville, VIC, Australia
Geoffrey I. McFadden: 4School of BioSciences, University of Melbourne, Parkville, VIC, Australia
Danny W. Wilson: Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia
Danny W. Wilson: Healthy Mothers, Healthy Babies Program, Burnet Institute, Melbourne, VIC, Australia
Danny W. Wilson: 2Australian Centre for Antimicrobial Resistance Ecology, The University of Adelaide, Adelaide, SA, Australia

DOI: https://doi.org/10.3389/fcimb.2022.1063407
Journal volume & issue: Vol. 12

Abstract

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IntroductionThe spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the apicoplast, and ‘quick-killing’ that kills rapidly across the entire blood stage development.MethodsHere, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans).ResultsSeventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment.DiscussionThe azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.

Published in Frontiers in Cellular and Infection Microbiology

ISSN: 2235-2988 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Science: Microbiology
Website: http://www.frontiersin.org/Cellular-and-Infection-Microbiology

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