Targeting malaria parasites with novel derivatives of azithromycin
- Author(s)
- Burns, AL; Sleebs, BE; Gancheva, M; McLean, KT; Siddiqui, G; Venter, H; Beeson, JG; O'Handley, R; Creek, DJ; Ma, S; Frölich, S; Goodman, CD; McFadden, GI; Wilson, DW;
- Journal Title
- Frontiers in Cellular and Infection Microbiology
- 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 quick-killing antimalarial activity.
- Publisher
- Frontiers Media
- Keywords
- Animals; Humans; Antimalarials/pharmacology; Azithromycin/pharmacology; Parasites; Plasmodium falciparum; Malaria, Falciparum/drug therapy/parasitology; Chloroquine/pharmacology/therapeutic use; Malaria/drug therapy/parasitology; Plasmodium; antimalarial; azithromycin; malaria; quick-killing
- Research Division(s)
- Chemical Biology
- PubMed ID
- 36530422
- Publisher's Version
- https://doi.org/10.3389/fcimb.2022.1063407
- Open Access at Publisher's Site
https://doi.org/10.3389/fcimb.2022.1063407- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-12-22 08:38:53
Last Modified: 2022-12-22 08:51:08