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Retargeting azithromycin analogues to have dual-modality antimalarial activity
Amy L Burns1, Brad E Sleebs2,3, Ghizal Siddiqui4
1Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.
BMC Biology
|September 30, 2020
Summary
New azithromycin analogues rapidly kill malaria parasites, offering a potent, fast-acting treatment. These modified macrolides show promise against drug-resistant malaria strains, addressing urgent global health needs.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Antimalarial drug resistance necessitates novel treatment strategies.
- Azithromycin shows slow-killing activity and suboptimal monotherapy efficacy.
- Chemical modification of azithromycin can enhance antimalarial potency and speed.
Purpose of the Study:
- To develop novel azithromycin analogues with improved speed and potency against malaria parasites.
- To investigate the mechanism of action of these new antimalarial compounds.
Main Methods:
- Synthesis and screening of 84 azithromycin analogues.
- In vitro testing against Plasmodium parasites, including resistant strains.
- Metabolomic profiling to elucidate mechanism of action.
Main Results:
- Identified analogues with nanomolar quick-killing potency against early-stage parasites.
- Achieved up to 1600-fold increased potency compared to azithromycin.
- Demonstrated efficacy against Plasmodium knowlesi and resistant Plasmodium falciparum.
- Discovered a multi-factorial quick-killing mechanism independent of apicoplast targeting.
Conclusions:
- Azithromycin analogues can rapidly kill asexual blood-stage malaria parasites.
- These compounds offer a multifactorial chemotype with both quick-killing and delayed-death mechanisms.
- Development of these analogues presents a promising new avenue for malaria treatment.
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