Publication:
Discovery and in vitro characterization of bioactive compounds against human fungal pathogens
Discovery and in vitro characterization of bioactive compounds against human fungal pathogens
dc.contributor.advisor | Ortiz Bermúdez, Patricia | |
dc.contributor.author | Jiménez Socha, María Alejandra | |
dc.contributor.college | College of Engineering | |
dc.contributor.committee | Schüller, Andreas | |
dc.contributor.committee | Domenech García, Maribella | |
dc.contributor.committee | Rivera Portalatín, Nilka | |
dc.contributor.department | Department of Chemical Engineering | |
dc.contributor.representative | Parés Matos, Elsie I. | |
dc.date.accessioned | 2023-07-17T15:19:41Z | |
dc.date.available | 2023-07-17T15:19:41Z | |
dc.date.issued | 2023-07-07 | |
dc.description.abstract | The Global Action for Fungal Infections has reported about 300 million cases of fungal infections worldwide, with two million deaths annually, mostly in immunocompromised patients. The scarcity of antifungal drugs and the increasing number of immunocompromised patients demand novel antifungal agents. We used a computational approach based on drug-drug-target networks to discover and characterize potential antifungal agents, determining the minimum inhibitory concentration (MIC) required to inhibit fungal growth. We identified 200 compounds with potential antifungal activity by adding a manually curated database of antifungal compounds using a drug repurposing approach and selected eight compounds with different clinical indications for experimental validation. Antifungal susceptibility assays demonstrated that Afimoxifene, Bithionol, Vortioxetine, and Zuclopenthixol inhibited the growth of human fungal pathogens within a concentration range of 8-64 µg/mL. We performed time-kill assays with Vortioxetine and Zuclopenthixol at 80% of their MIC, showing death rates of 0.417 h-1 and 0.253 h-1, respectively, against Candida albicans. In vitro cytotoxicity tests on NIH3T3 cells revealed cytotoxic effects of Vortioxetine and Zuclopenthixol over a concentration range of 12 -128 µg/mL. HepG2 cells exhibited higher resistance, with an IC25 of 104.856 ± 0.854 µg/mL for Vortioxetine and 52.280 ± 0.370 µg/mL for Zuclopenthixol. Our results corroborated the antifungal activity of the two new compounds and provided complementary information to the literature through in vitro assays. We performed combination treatments with Fluconazole to enhance efficacy by reducing the effective concentration. These findings highlight the potential of the selected compounds as promising candidates for the development of novel antifungal compounds. | |
dc.description.abstract | La Acción Global para las Infecciones Fúngicas ha informado sobre 300 millones de casos de infecciones fúngicas en todo el mundo, con dos millones de muertes al año, principalmente en pacientes inmunocomprometidos. La escasez de compuestos antifúngicos y el aumento de pacientes inmunocomprometidos demandan nuevos agentes antifúngicos. Utilizamos un enfoque computacional basado en redes de fármaco-fármaco-objetivo para descubrir y caracterizar posibles agentes antifúngicos y determinamos la concentración mínima inhibitoria (CMI) necesaria para inhibir el crecimiento fúngico. Identificamos 200 compuestos con potencial actividad antifúngica con la adición de una base de datos de compuestos antifúngicos curada manualmente utilizando reposicionamiento de drogas y seleccionamos ocho compuestos con diferentes indicaciones clínicas para validación experimental. Los ensayos de susceptibilidad antifúngica demostraron que Afimoxifeno, Bitionol, Vortioxetina y Zuclopentixol inhibieron el crecimiento de hongos patógenos humanos en un rango de concentraciones de 8-64 µg/mL. Realizamos ensayos de tiempo de muerte con Vortioxetina y Zuclopentixol al 80% de su CIM, mostrando tasas de muerte de 0.417 h-1 y 0.253 h-1, respectivamente, para Cándida albicans. En pruebas de citotoxicidad in vitro en células NIH3T3, Vortioxetina y Zuclopentixol mostraron efectos citotóxicos en un rango de concentración de 12 -128 µg/mL. Las células HepG2 presentaron una mayor resistencia, con una IC25 de 104.856 ± 0.854 µg/mL para Vortioxetina y 52.280 ± 0.370 µg/mL para Zuclopentixol. Nuestros resultados corroboraron la actividad antifúngica de los dos nuevos compuestos y por medio de ensayos in vitro se complementó la información reportada en la literatura. Realizamos tratamientos combinados con Fluconazol para potenciar su eficacia, reduciendo su concentración efectiva. Estos hallazgos destacan el potencial de los compuestos seleccionados como candidatos prometedores para el desarrollo de nuevos compuestos antifúngicos. | |
dc.description.graduationSemester | Summer | |
dc.description.graduationYear | 2023 | |
dc.description.sponsorship | Chemical Engineering Department at UPRM for providing the necessary funding for my master's degree. The financial support I received from this department was crucial for me to continue my academic training | |
dc.identifier.uri | https://hdl.handle.net/20.500.11801/3557 | |
dc.language.iso | en | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.holder | (c) 2023 Maria Alejandra Jimenez Socha | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Fungal Pathogens | |
dc.subject | Antifungal Drugs | |
dc.subject | Drug repurposing | |
dc.subject.lcsh | Antifungal agents | |
dc.subject.lcsh | Pathogenic fungi | |
dc.subject.lcsh | Drugs - Design | |
dc.subject.lcsh | Bioactive compounds | |
dc.subject.lcsh | Drugs - Statistical methods - Computer programs | |
dc.title | Discovery and in vitro characterization of bioactive compounds against human fungal pathogens | |
dc.type | Thesis | |
dspace.entity.type | Publication | |
thesis.degree.discipline | Chemical Engineering | |
thesis.degree.level | M.S. |