ArticleBMC biology2020
Retargeting azithromycin analogues to have dual-modality antimalarial activity.
Article in BMC biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Effect of Antenatal Monthly Sulfadoxine-Pyrimethamine, Alone or with Azithromycin, on Gestational Weight Gain and Anemia during Pregnancy and One Month Postpartum in Malawi: A Randomized Controlled Trial Secondary Analysis.The American journal of tropical medicine and hygiene · 2025Trial
- Malaria positivity following a single oral dose of azithromycin among children in Burkina Faso: a randomized controlled trial.BMC infectious diseases · 2022Trial
- Characterizing the quick-killing mechanism of action of azithromycin analogs against malaria parasites.Antimicrobial agents and chemotherapy · 2025Article
- A review of natural products as a source of next-generation drugs against apicomplexan parasites.npj antimicrobials and resistance · 2025Review
- The roles of COX-2 in protozoan infection.Frontiers in immunology · 2023Review
- A determination of pan-pathogen antimicrobials?Medicine in drug discovery · 2022Review
- Targeting malaria parasites with novel derivatives of azithromycin.Frontiers in cellular and infection microbiology · 2022Article
- Antimalarial Natural Products.Progress in the chemistry of organic natural products · 2022Article
- Clinical management of Plasmodium knowlesi malaria.Advances in parasitology · 2021Review
- Methods Used to Investigate theFrontiers in cellular and infection microbiology · 2021Review
- Multipurpose Drugs Active Against BothFrontiers in cellular and infection microbiology · 2021Review
- Article
- The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields.Drug target insightsReview
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundResistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing 'delayed-death' activity against the parasite's apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action.
resultsInvestigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on 'quick-killing' activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity.
conclusionWe show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.