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

TITLE=Targeting malaria parasites with novel derivatives of azithromycin

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.1063407

DOI=10.3389/fcimb.2022.1063407

ISSN=2235-2988

ABSTRACT=<sec><title>Introduction</title><p>The spread of artemisinin resistant <italic>Plasmodium falciparum</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 <italic>via</italic> 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.</p></sec><sec><title>Methods</title><p>Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against <italic>P. falciparum</italic> (the most virulent human malaria) and <italic>P. knowlesi</italic> (a monkey parasite that frequently infects humans).</p></sec><sec><title>Results</title><p>Seventeen analogues showed improved quick-killing against both <italic>Plasmodium</italic> species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for <italic>P. falciparum</italic> and <italic>P. knowlesi</italic>, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of <italic>P. falciparum</italic> parasites (&lt;12 hrs treatment) and were &gt;5-fold more selective against <italic>P. falciparum</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 <italic>Toxoplasma gondii</italic> and the gram-positive bacterium <italic>Streptococcus pneumoniae</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.</p></sec><sec><title>Discussion</title><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.</p></sec>