{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:10:53Z","timestamp":1790251853136,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The spread of artemisinin resistant <jats:italic>Plasmodium falciparum<\/jats:italic> 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 <jats:italic>via<\/jats:italic> two mechanisms: \u2018delayed death\u2019 by inhibiting the bacterium-like ribosomes of the apicoplast, and \u2018quick-killing\u2019 that kills rapidly across the entire blood stage development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against <jats:italic>P. falciparum<\/jats:italic> (the most virulent human malaria) and <jats:italic>P. knowlesi<\/jats:italic> (a monkey parasite that frequently infects humans).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seventeen analogues showed improved quick-killing against both <jats:italic>Plasmodium<\/jats:italic> species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for <jats:italic>P. falciparum<\/jats:italic> and <jats:italic>P. knowlesi<\/jats:italic>, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of <jats:italic>P. falciparum<\/jats:italic> parasites (&amp;lt;12 hrs treatment) and were &amp;gt;5-fold more selective against <jats:italic>P. falciparum<\/jats:italic> 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 <jats:italic>Toxoplasma gondii<\/jats:italic> and the gram-positive bacterium <jats:italic>Streptococcus pneumoniae<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>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 quick-killing antimalarial activity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.1063407","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T07:37:38Z","timestamp":1669793858000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting malaria parasites with novel derivatives of azithromycin"],"prefix":"10.3389","volume":"12","author":[{"given":"Amy L.","family":"Burns","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad E.","family":"Sleebs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gancheva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley T.","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghizal","family":"Siddiqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrietta","family":"Venter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G.","family":"Beeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"O\u2019Handley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren J.","family":"Creek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shutao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Fr\u00f6lich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey I.","family":"McFadden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny W.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1242\/jcs.061499","article-title":"Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum","volume":"123","author":"Abu Bakar","year":"2010","journal-title":"J. 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