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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 µg/mL for C. krusei and of 128 µg/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 μg/mL and a HC10 value against human red blood cells of 0.8 μg/mL.

Details

Title
Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei
Author
Costa, Inês 1   VIAFID ORCID Logo  ; Lopes, Inês 2 ; Morais, Mariana 3   VIAFID ORCID Logo  ; Silva, Renata 1   VIAFID ORCID Logo  ; Remião, Fernando 1   VIAFID ORCID Logo  ; Medeiros, Rui 4   VIAFID ORCID Logo  ; Alves, Luís G 5   VIAFID ORCID Logo  ; Pinto, Eugénia 6   VIAFID ORCID Logo  ; Cerqueira, Fátima 4   VIAFID ORCID Logo 

 UCIBIO—Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313 Porto, Portugal; [email protected] (I.C.); [email protected] (R.S.); [email protected] (F.R.); Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 
 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; [email protected] (I.L.); [email protected] (M.M.); [email protected] (R.M.); [email protected] (F.C.); School of Health, Polytechnic Institute of Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal 
 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; [email protected] (I.L.); [email protected] (M.M.); [email protected] (R.M.); [email protected] (F.C.); ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal 
 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; [email protected] (I.L.); [email protected] (M.M.); [email protected] (R.M.); [email protected] (F.C.); FP-I3ID, FP-BHS, GIT-LoSa, University Fernando Pessoa, Praça 9 de Abril 349, 4249-004 Porto, Portugal; Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal 
 Centro de Química Estrutural—Institute of Molecular Sciences, Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento, Av. António José de Almeida nº 12, 1000-043 Lisboa, Portugal; [email protected] 
 Laboratory of Microbiology, Biological Sciences Department, Faculty of Pharmacy of University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal 
First page
5209
Publication year
2024
Publication date
2024
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3059434797
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.