Targeting malaria parasites with novel derivatives of azithromycin

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

doi:10.3389/fcimb.2022.1063407

Targeting malaria parasites with novel derivatives of azithromycin

Front Cell Infect Microbiol. 2022 Nov 30:12:1063407. doi: 10.3389/fcimb.2022.1063407. eCollection 2022.

Authors

Amy L Burns^{1

2}, Brad E Sleebs^{3

4}, Maria Gancheva¹, Kimberley T McLean¹, Ghizal Siddiqui⁵, Henrietta Venter⁶, James G Beeson^{7

8

9

10}, Ryan O'Handley^{11

12}, Darren J Creek⁵, Shutao Ma¹³, Sonja Frölich¹, Christopher D Goodman¹⁴, Geoffrey I McFadden¹⁴, Danny W Wilson^{1

7

12}

Affiliations

¹ Research Centre for Infectious Diseases, School of Biological Sciences, the University of Adelaide, Adelaide, SA, Australia.
² School of Science and Technology, the University of New England, Armidale, NSW, Australia.
³ ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
⁴ Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
⁵ Drug Delivery Disposition and Dynamics, Monash University, Parkville, VIC, Australia.
⁶ Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
⁷ Healthy Mothers, Healthy Babies Program, Burnet Institute, Melbourne, VIC, Australia.
⁸ Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
⁹ Central Clinical School, Monash University, Melbourne, Vic, Australia.
¹⁰ Department of Microbiology, Monash University, Melbourne, Vic, Australia.
¹¹ School of Animal and Veterinary Science, University of Adelaide, Adelaide, SA, Australia.
¹² Australian Centre for Antimicrobial Resistance Ecology, The University of Adelaide, Adelaide, SA, Australia.
¹³ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
¹⁴ School of BioSciences, University of Melbourne, Parkville, VIC, Australia.

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.

Keywords: Plasmodium; antimalarial; azithromycin; malaria; quick-killing.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antimalarials* / pharmacology
Azithromycin / pharmacology
Chloroquine / pharmacology
Chloroquine / therapeutic use
Humans
Malaria* / drug therapy
Malaria* / parasitology
Malaria, Falciparum* / drug therapy
Malaria, Falciparum* / parasitology
Parasites*
Plasmodium falciparum

Substances

Antimalarials
Azithromycin
Chloroquine

Grants and funding

U2C DK119886/DK/NIDDK NIH HHS/United States