{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:21:23Z","timestamp":1787736083753,"version":"build-2784847793"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Parasitol."],"abstract":"<jats:p>\n                    Protozoan parasitic infections, including malaria, leishmaniasis, and human African trypanosomiasis, remain major global public health challenges. In the absence of highly effective vaccines, disease control relies primarily on chemotherapy; however, the emergence and spread of drug-resistant parasite populations increasingly threaten treatment efficacy. This review synthesizes current evidence on the molecular mechanisms underlying drug resistance in\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    ,\n                    <jats:italic>Leishmania<\/jats:italic>\n                    , and\n                    <jats:italic>Trypanosoma<\/jats:italic>\n                    species through a systematic analysis of literature. The review identifies four interconnected mechanisms that drive the evolution of drug resistance. First, altered drug transport enables parasites to regulate intracellular drug concentrations through mutations, loss, or amplification of membrane transporters, including PfCRT in\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    and AQP2 in\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    . Second, target modification and genomic plasticity promote resistance through point mutations in drug targets, such as\n                    <jats:italic>dhfr<\/jats:italic>\n                    and\n                    <jats:italic>dhps<\/jats:italic>\n                    in\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    , while kinetoplastids, particularly\n                    <jats:italic>Leishmania<\/jats:italic>\n                    , exploit extensive genomic plasticity, including aneuploidy, gene amplification, and translational reprogramming, to facilitate rapid adaptation under drug pressure. Third, metabolic reprogramming enhances parasite survival by increasing intracellular thiol production, strengthening antioxidant defense systems, and reshaping central carbon and lipid metabolism to mitigate drug-induced stress. Finally, stress response and persistence mechanisms enable subpopulations of parasites to enter dormant, persister-like states characterized by reduced metabolic activity and slowed proliferation, thereby evading both host immune responses and chemotherapeutic agents. Collectively, these findings demonstrate that drug resistance is a dynamic, multifactorial evolutionary process rather than a single molecular event. Addressing this growing challenge requires integrating genomic surveillance, molecular diagnostics, mathematical modeling of resistance transmission, and mechanistic insights into parasite persistence into future drug discovery and disease control strategies. Such an integrated approach is essential for improving the durability of antiprotozoal therapies and advancing global efforts to control neglected protozoan diseases.\n                  <\/jats:p>","DOI":"10.3389\/fpara.2026.1934996","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:46:53Z","timestamp":1787734013000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular mechanisms underlying drug resistance in protozoan parasites: emerging mechanisms and therapeutic perspectives"],"prefix":"10.3389","volume":"5","author":[{"given":"Kavithma","family":"Uduwela","sequence":"first","affiliation":[{"name":"Department of Zoology and Environmental Management, Faculty of Science, University of Kelaniya","place":["Kelaniya, Sri Lanka"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshila","family":"Ranasinghe","sequence":"additional","affiliation":[{"name":"Department of Zoology and Environmental Management, Faculty of Science, University of Kelaniya","place":["Kelaniya, Sri Lanka"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature10771","article-title":"High-throughput decoding of antiTrypanosomal drug efficacy and resistance","volume":"482","author":"Alsford","year":"2012","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2013","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"10996","DOI":"10.1073\/pnas.1202885109","article-title":"Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes","volume":"109","author":"Baker","year":"2012","journal-title":"Proc. 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