{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:01:07Z","timestamp":1788314467924,"version":"build-2803163510"},"reference-count":234,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:00:00Z","timestamp":1772841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Human Resources Training Project to Support the Development of Clinical Research in Brazil","award":["88887.800.657\/2022-00"],"award-info":[{"award-number":["88887.800.657\/2022-00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Devastating or nearly invariably fatal infections caused by free-living amoebae (FLA), including Acanthamoeba keratitis (AK), granulomatous amoebic encephalitis (GAE), and primary amoebic meningoencephalitis (PAM), remain a significant public health concern, driven by increasing case numbers, geographic expansion, and the lack of approved, effective, and safe treatments. Despite decades of research, no new drugs have been successfully approved, highlighting the severe limitations of de novo drug development for these infections, particularly for GAE and PAM, largely due to the challenges of conducting clinical trials for these rare and rapidly lethal diseases. In this context, drug repurposing represents a cost-effective and promising strategy to accelerate therapeutic advances and overcome key bottlenecks of conventional drug development. Accordingly, we conducted a systematic review of in vitro studies and animal models of AK, GAE, and PAM reported in indexed databases to identify promising drug repurposing candidates against FLA infections. After screening 23,624 records, 112 studies were included in the analysis. Overall, 2726 drugs and drug combinations, spanning 865 pharmacological classes and approved for 565 therapeutic indications, were assessed for their repurposing potential. Among these, 166 compounds showed substantial trophocidal activity (\u2265IC50) at potentially translatable concentrations (\u226410 \u00b5M), including six with additional cysticidal activity. In vitro, four compounds were active against Balamuthia mandrillaris, 44 against Acanthamoeba spp. (three cysticidal), and 115 against Naegleria spp. (three cysticidal). In in vivo studies, sulfadiazine and rifampicin were effective as preventive or early monotherapies for GAE. For AK, the combination of polyhexamethylene biguanide, neomycin, and atropine, as well as voriconazole and nitazoxanide monotherapies, showed the greatest promise. In PAM, azithromycin alone or in combination with amphotericin B emerged as the most promising therapeutic options. Further studies are required to advance the clinical translatability of these findings. To the best of our knowledge, this work provides the first comprehensive and integrated synthesis of repurposable drug candidates against FLA infections.<\/jats:p>","DOI":"10.3390\/pathogens15030294","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:16:12Z","timestamp":1773051372000},"page":"294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Promising Drug Repurposing Candidates Targeting Free-Living Amoebae: A Systematic and Critical Review of Laboratory-Based Evidence"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9440-3227","authenticated-orcid":false,"given":"Beni Jequicene Mussengue","family":"Cha\u00faque","sequence":"first","affiliation":[{"name":"Master\u2019s Program in Clinical Research, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil"},{"name":"Postgraduate Program in Biological Sciences\u2014Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"},{"name":"Center of Studies in Science and Technology (NECET), Biology Course, Universidade Rovuma, Lichinga P.O. Box 04, Niassa, Mozambique"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2271-2559","authenticated-orcid":false,"given":"Luiza Bernardes","family":"Chagas","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaisla Cristiane Borella","family":"da Silva","sequence":"additional","affiliation":[{"name":"Protozoology Laboratory, Microbiology Immunology and Parasitology Department, Basic Health Sciences Institute, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise Leal","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Master\u2019s Program in Clinical Research, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6888-192X","authenticated-orcid":false,"given":"Luciano Palmeiro","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Master\u2019s Program in Clinical Research, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil"},{"name":"Physiotherapy Course, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile da Silva Lins","family":"Ba\u00eda","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biological Sciences\u2014Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoella Kessler Gomes","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre 90610-970, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1222-4557","authenticated-orcid":false,"given":"Guilherme Brittes","family":"Benitez","sequence":"additional","affiliation":[{"name":"Industrial and Systems Engineering Graduate Program, Polytechnic School, Pontifical Catholic University of Parana (PUCPR), Curitiba 80215-901, PR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais Lemos","family":"Mendes","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biological Sciences\u2014Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8614-394X","authenticated-orcid":false,"given":"Hellen Kempfer","family":"Philippsen","sequence":"additional","affiliation":[{"name":"Socio-Environmental and Water Resources Institute, Federal Rural University of the Amazon (UFRA), Bel\u00e9m 66077-830, PA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Dalla","family":"Rosa","sequence":"additional","affiliation":[{"name":"Central Laboratory for Avian Disease Diagnosis, Department of Preventive Veterinary Medicine, Center for Rural Sciences, Universidade Federal de Santa Maria, Santa Maria 97105-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5948-472X","authenticated-orcid":false,"given":"Fabr\u00edcio Souza","family":"Campos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica & Biotecnologia, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"},{"name":"Department of Public & Ecosystem Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilise Brittes","family":"Rott","sequence":"additional","affiliation":[{"name":"Protozoology Laboratory, Microbiology Immunology and Parasitology Department, Basic Health Sciences Institute, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4432-2231","authenticated-orcid":false,"given":"R\u00e9gis Adriel","family":"Zanette","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biological Sciences\u2014Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-6594","authenticated-orcid":false,"given":"Jos\u00e9 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