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Type: Journal article
Title: Targeting malaria parasites with novel derivatives of azithromycin
Author: Burns, A.L.
Sleebs, B.E.
Gancheva, M.
McLean, K.T.
Siddiqui, G.
Venter, H.
Beeson, J.G.
O’Handley, R.
Creek, D.J.
Ma, S.
Frölich, S.
Goodman, C.D.
McFadden, G.I.
Wilson, D.W.
Citation: Frontiers in Cellular and Infection Microbiology, 2022; 12
Publisher: Frontiers Media SA
Issue Date: 2022
ISSN: 2235-2988
Statement of
Amy L. Burns, Brad E. Sleebs, Maria Gancheva, Kimberley T. McLean, Ghizal Siddiqui, Henrietta Venter, James G. Beeson, Ryan O, Handley, Darren J. Creek, Shutao Ma, Sonja Frölich, Christopher D. Goodman, Geoffrey I. McFadden, and Danny W. Wilson
Abstract: Introduction: The 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. Methods: Here, 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). Results: Seventeen 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. Discussion: The 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 quickkilling antimalarial activity.
Keywords: malaria; antimalarial; azithromycin; quick-killing; Plasmodium
Rights: © 2022 Burns, Sleebs, Gancheva, McLean, Siddiqui, Venter, Beeson, O’Handley, Creek, Ma, Frölich, Goodman, McFadden and Wilson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI: 10.3389/fcimb.2022.1063407
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Appears in Collections:Biochemistry publications

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