Journal Article

Targeting malaria parasites with novel derivatives of azithromycin

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

2022

Overview

The spread of artemisinin resistant 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 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. Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against (the most virulent human malaria) and (a monkey parasite that frequently infects humans). Seventeen analogues showed improved quick-killing against both species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for and , respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of parasites (<12 hrs treatment) and were >5-fold more selective against 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 and the gram-positive bacterium 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. 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 SA,Frontiers Media S.A
• Subject: Animals / Antibiotics / antimalarial / Antimalarial activity / Antimalarials - pharmacology / Antiparasitic agents / Artemisinin / Azithromycin / Azithromycin - pharmacology / Bacteria / Bacterial infections / Biosynthesis / Blood parasites / Cellular and Infection Microbiology / Chloroquine / Chloroquine - pharmacology / Chloroquine - therapeutic use / Developmental stages / Drugs / Gram-positive bacteria / Hemoglobin / Humans / Malaria / Malaria - drug therapy / Malaria - parasitology / Malaria, Falciparum - drug therapy / Malaria, Falciparum - parasitology / Metabolomics / Parasite resistance / Parasites / Peptides / Plasmodium / Plasmodium falciparum / Proteins / quick-killing / Ribonucleic acid / Ribosomes / RNA