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Amidst the health crisis caused by the rise of multi-resistant pathogenic microorganisms, Antimicrobial Peptides (AMPs) have emerged as a potential alternative to traditional antibiotics. In this sense, Cm-p5 is an AMP with fungistatic activity against the yeast Candida albicans. Its antimicrobial activity and selectivity have been well characterized; however, the mechanism of action is still unknown. This study used biophysical approaches to gain insight into how this peptide exerts its activity. Stability and fluidity of lipid membrane were explored by liposome leakage and Laurdan generalized polarization (GP) respectively, suggesting that Cm-p5 does not perturb lipid membranes even at very high concentrations (≥100 µm.L -1 ). Likewise, no depolarizing action was observed using 3,3'-propil-2,2'-thyodicarbocianine, a potential membrane fluorescent reporter, with C. albicans cells or the corresponding liposome models. Changes in liposome size were analyzed by Dynamic Light Scattering (DLS) data, indicating that Cm-p5 covers the vesicular surface slightly increasing liposome hydrodynamic size, without liposome rupture. These results were further corroborated with Langmuir monolayer isotherms, where no significant changes in lateral pressure or area per lipid were detected, indicating little or no insertion. Finally, data obtained from molecular dynamics simulations aligned with in vitro observations, whereby Cm-p5 slightly interacted with the fungal membrane model surface without causing significant perturbation. These results suggest Cm-p5 is not a pore-forming anti-fungal peptide and that other mechanisms of action on the membrane as some limitation of fungal nutrition or receptor-dependent transduction for depressing growth development should be explored., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carlos Munoz-Garay reports financial support was provided by UNAM-DGAPA-PAPIIT grant IN210921 and IN222624. Carlos Munoz-Garay reports financial support was provided by Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo (CYTED), (219RT0573). Red temática en salud. Desarrollo de péptidos antivirales y antimicrobianos para cepas multi-resistentes. Carlos Munoz-Garay reports administrative support and equipment, drugs, or supplies were provided by Dirección General de Cómputo y de Tecnologías de Información y Comunicación, by MIZTLI time machine grant LANCAD-UNAM-DGTIC-203. Anselmo de Jesus Otero-Gonzalez reports financial support was provided by German Research Society (DFG) Project-ID316249678-CRC1279. Anselmo de Jesus Otero-Gonzalez reports financial support was provided by DAAD-German Ministry for Foreign Affairs via the program Global Health and Pandemic Prevention Centers. Octavio Luiz Franco reports financial support was provided by Fundação de Apoio à Pesquisa do Distrito Federal (FAPDF). Octavio Luiz Franco reports financial support was provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Octavio Luiz Franco reports financial support was provided by Conselho Nacional de Desenvolvimento e Tecnológico (CNPq). Octavio Luiz Franco reports financial support was provided by Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT). R.F.V recieved funding from CONICET PIBAA 2022–1014 and ANPCyT PICT 2020–03526.If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)