Characterizing the quick-killing mechanism of action of azithromycin analogs against malaria parasites

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dc.contributor.authorMao, E.Y.
dc.contributor.authorNguyen, W.
dc.contributor.authorJana, G.P.
dc.contributor.authorMaity, B.C.
dc.contributor.authorPazicky, S.
dc.contributor.authorGiannangelo, C.
dc.contributor.authorReader, J.
dc.contributor.authorFamodimu, M.T.
dc.contributor.authorBirkholtz, L.-M.
dc.contributor.authorDelves, M.J.
dc.contributor.authorCreek, D.J.
dc.contributor.authorBozdech, Z.
dc.contributor.authorLaleu, B.
dc.contributor.authorBurrows, J.N.
dc.contributor.authorSleebs, B.E.
dc.contributor.authorGancheva, M.R.
dc.contributor.authorWilson, D.W.
dc.contributor.editorOdom John, A.
dc.date.issued2025
dc.description.abstractDrug resistance is steadily undermining the efficacy of frontline anti-malarials, highlighting the urgent need for novel therapies with alternative mechanisms of action. The chemical addition of different moieties to azithromycin yields compounds with improved quick-killing potency against malaria parasites, with the most active analogs typically containing a chloroquinoline group. Here, we investigated the quick-killing mechanism of five azithromycin analogs, two of which contain differentially oriented chloroquinoline moieties. The improvement in quick-killing activity over azithromycin for non-chloroquinoline analogs was around 10 -to 42-fold, with chloroquinoline-containing analogs showing a further 2- to 17-fold improvement over non-chloroquinoline compounds. Chemical inhibition of hemoglobin digestion and chloroquine’s inhibitory effect against heme polymerization linked analogs with both chloroquinoline and non-chloroquinoline modifications to a chloroquine-like mechanism of action. However, none of the analogs showed a significant reduction in efficacy against chloroquine-resistant asexual blood-stage parasites. Multiple attempts at selecting for azithromycin analog-resistant parasites to elucidate the mechanism of quick-killing were unsuccessful. Application of cellular thermal shift proteomics revealed that azithromycin analogs significantly stabilized 34–155 different proteins in trophozoites, a high number that showed minimal overlap with chloroquine. Additionally, our most potent chloroquinoline-containing analog demonstrated a significant improvement in gametocytocidal activity over azithromycin and further maintained moderate inhibition of chloroquine-insensitive late-stage gametocytes. These findings support that this class of azithromycin analogs kills malaria parasites through a broad range of potential mechanisms, making them promising candidates for optimization as fast and broad-acting anti-malarials.
dc.description.statementofresponsibilityEmma Y. Mao, William Nguyen, Gouranga P. Jana, Bikash C. Maity, Samuel Pazicky, Carlo Giannangelo, Janette Reader, Mufuliat T. Famodimu, Lyn-Marie Birkholtz, Michael J. Delves, Darren J. Creek, Zbynek Bozdech, Benoît Laleu, Jeremy N.Burrows, Brad E. Sleebs, Maria R. Gancheva, Danny W. Wilson
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2025; 69(9):e0178324-1-e0178324-27
dc.identifier.doi10.1128/aac.01783-24
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.orcidMao, E.Y. [0000-0001-8709-1897] [0000-0002-4040-1381]
dc.identifier.orcidGancheva, M.R. [0000-0001-7428-6791]
dc.identifier.orcidWilson, D.W. [0000-0002-5073-1405]
dc.identifier.urihttps://hdl.handle.net/2440/147759
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1143974
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1135421
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1185354
dc.relation.granthttp://purl.org/au-research/grants/arc/IC220100050
dc.rights© 2025 Mao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.source.urihttps://doi.org/10.1128/aac.01783-24
dc.subjectantimalarial agents
dc.subjectazithromycin
dc.subjectcellular thermal shift assay
dc.subjectmalaria
dc.subjectPlasmodium
dc.titleCharacterizing the quick-killing mechanism of action of azithromycin analogs against malaria parasites
dc.typeJournal article
pubs.publication-statusPublished online

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