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(Australia)","award":["UIDB\/04423\/2020"],"award-info":[{"award-number":["UIDB\/04423\/2020"]}]},{"name":"Wellcome Trust (UK) and The University of Queensland (Australia)","award":["UIDP\/04423\/2020"],"award-info":[{"award-number":["UIDP\/04423\/2020"]}]},{"name":"Wellcome Trust (UK) and The University of Queensland (Australia)","award":["PI86-CI-IPOP-66-2019"],"award-info":[{"award-number":["PI86-CI-IPOP-66-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mycoses are one of the major causes of morbidity\/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 \u00b5g\/mL for C. krusei and of 128 \u00b5g\/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin\/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 \u03bcg\/mL and a HC10 value against human red blood cells of 0.8 \u03bcg\/mL.<\/jats:p>","DOI":"10.3390\/ijms25105209","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:03:08Z","timestamp":1715673788000},"page":"5209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7454-9878","authenticated-orcid":false,"given":"In\u00eas","family":"Costa","sequence":"first","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira n\u00ba 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"In\u00eas","family":"Lopes","sequence":"additional","affiliation":[{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), 4169-007 Porto, Portugal"},{"name":"School of Health, Polytechnic Institute of Porto, Rua Dr. Ant\u00f3nio Bernardino de Almeida 400, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8406-8210","authenticated-orcid":false,"given":"Mariana","family":"Morais","sequence":"additional","affiliation":[{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), 4169-007 Porto, Portugal"},{"name":"ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7548","authenticated-orcid":false,"given":"Renata","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira n\u00ba 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira n\u00ba 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-8373","authenticated-orcid":false,"given":"Rui","family":"Medeiros","sequence":"additional","affiliation":[{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), 4169-007 Porto, Portugal"},{"name":"FP-I3ID, FP-BHS, GIT-LoSa, University Fernando Pessoa, Pra\u00e7a 9 de Abril 349, 4249-004 Porto, Portugal"},{"name":"Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-9850","authenticated-orcid":false,"given":"Lu\u00eds G.","family":"Alves","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural\u2014Institute of Molecular Sciences, Associa\u00e7\u00e3o do Instituto Superior T\u00e9cnico para a Investiga\u00e7\u00e3o e Desenvolvimento, Av. Ant\u00f3nio Jos\u00e9 de Almeida n\u00ba 12, 1000-043 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-5809","authenticated-orcid":false,"given":"Eug\u00e9nia","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Biological Sciences Department, Faculty of Pharmacy of University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR\/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, Terminal de Cruzeiros do Porto de Leix\u00f5es, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4513-4654","authenticated-orcid":false,"given":"F\u00e1tima","family":"Cerqueira","sequence":"additional","affiliation":[{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), 4169-007 Porto, Portugal"},{"name":"FP-I3ID, FP-BHS, GIT-LoSa, University Fernando Pessoa, Pra\u00e7a 9 de Abril 349, 4249-004 Porto, Portugal"},{"name":"Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e255","DOI":"10.1093\/cid\/ciac489","article-title":"Increased Deaths From Fungal Infections During the Coronavirus Disease 2019 Pandemic-National Vital Statistics System, United States, January 2020\u2013December 2021","volume":"76","author":"Gold","year":"2023","journal-title":"Clin. 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