{"doi":"10.3389/fcimb.2022.1063407","title":"Targeting malaria parasites with novel derivatives of azithromycin","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.","journal":"Frontiers in Cellular and Infection Microbiology","year":2022,"id":274749,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":943289,"name":"Brad E. Sleebs","orcid":"0000-0001-9117-1048","position":1,"is_corresponding":false},{"id":943290,"name":"Maria R. Gancheva","orcid":"0000-0001-7428-6791","position":2,"is_corresponding":false},{"id":943291,"name":"Kimberley T. McLean","orcid":"0000-0001-6743-2527","position":3,"is_corresponding":false},{"id":304447,"name":"Ghizal Siddiqui","orcid":"0000-0002-3153-3198","position":4,"is_corresponding":false},{"id":943292,"name":"Henrietta Venter","orcid":"0000-0001-5569-7755","position":5,"is_corresponding":false},{"id":305203,"name":"James G. Beeson","orcid":"0000-0002-1018-7898","position":6,"is_corresponding":false},{"id":943293,"name":"Ryan O’Handley","orcid":"0000-0002-6046-0688","position":7,"is_corresponding":false},{"id":304456,"name":"Darren J. Creek","orcid":"0000-0001-7497-7082","position":8,"is_corresponding":false},{"id":943294,"name":"Shutao Ma","orcid":"0000-0003-1206-2375","position":9,"is_corresponding":false},{"id":943295,"name":"Sonja Frölich","orcid":"0000-0002-8673-3437","position":10,"is_corresponding":false},{"id":943296,"name":"C.D. Goodman","orcid":"0000-0002-8923-7594","position":11,"is_corresponding":false},{"id":574556,"name":"Geoffrey I. McFadden","orcid":"0000-0002-5351-1627","position":12,"is_corresponding":false},{"id":603595,"name":"Danny W. Wilson","orcid":"0000-0002-5073-1405","position":13,"is_corresponding":false},{"id":943787,"name":"Amy L. Burns","orcid":null,"position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T00:28:12.324621Z","pmid":"36530422","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}