Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa
Varios mecanismos están implicados en el desarrollo de la resistencia en cepas de Pseudomonas aeruginosa. Presiones selectivas han promovido numerosas estrategias de supervivencia bacteriana que han favorecido su adaptación a diversos ambientes (Lu et al., 2019, Tacconelli et al., 2018; Zhong et al....
- Autores:
-
López Piñeros, Laura Patricia
- Tipo de recurso:
- Fecha de publicación:
- 2022
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/81710
- Palabra clave:
- 540 - Química y ciencias afines
Pseudomonas aeruginosa
lasR
quorum sensing
biofilm
molecular docking
gene expression
biopelícula
acoplamiento molecular
expresión génica
- Rights
- openAccess
- License
- Reconocimiento 4.0 Internacional
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UNACIONAL2_15e4cddb10c8b3df02a6a378278f27ad |
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oai:repositorio.unal.edu.co:unal/81710 |
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UNACIONAL2 |
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Universidad Nacional de Colombia |
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|
| dc.title.spa.fl_str_mv |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| dc.title.translated.eng.fl_str_mv |
Identification of inhibitory molecules in the expression of lasR as a regulator of the Quorum Sensing in Pseudomonas aeruginosa |
| title |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| spellingShingle |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa 540 - Química y ciencias afines Pseudomonas aeruginosa lasR quorum sensing biofilm molecular docking gene expression biopelícula acoplamiento molecular expresión génica |
| title_short |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| title_full |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| title_fullStr |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| title_full_unstemmed |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| title_sort |
Identificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosa |
| dc.creator.fl_str_mv |
López Piñeros, Laura Patricia |
| dc.contributor.advisor.none.fl_str_mv |
López Vallejo, Fabián Harvey |
| dc.contributor.advisor.spa.fl_str_mv |
Hernández Rodríguez, Patricia |
| dc.contributor.author.none.fl_str_mv |
López Piñeros, Laura Patricia |
| dc.contributor.researchgroup.spa.fl_str_mv |
Grupo de Investigación en Química de Productos Naturales Vegetales Bioactivos (Quipronab) |
| dc.subject.ddc.spa.fl_str_mv |
540 - Química y ciencias afines |
| topic |
540 - Química y ciencias afines Pseudomonas aeruginosa lasR quorum sensing biofilm molecular docking gene expression biopelícula acoplamiento molecular expresión génica |
| dc.subject.proposal.none.fl_str_mv |
Pseudomonas aeruginosa lasR |
| dc.subject.proposal.eng.fl_str_mv |
quorum sensing biofilm molecular docking gene expression |
| dc.subject.proposal.spa.fl_str_mv |
biopelícula acoplamiento molecular expresión génica |
| description |
Varios mecanismos están implicados en el desarrollo de la resistencia en cepas de Pseudomonas aeruginosa. Presiones selectivas han promovido numerosas estrategias de supervivencia bacteriana que han favorecido su adaptación a diversos ambientes (Lu et al., 2019, Tacconelli et al., 2018; Zhong et al., 2020). Uno de los mecanismos de interés es el sistema conocido como quorum sensing (QS) por el que las bacterias se comunican a través de moléculas de señalización (Ouyang et al., 2016; Vasavi et al., 2017). Una vez que las bacterias han alcanzado una alta densidad poblacional, éstas controlan la producción de varios factores de virulencia extracelular y la formación de biopelículas proporcionando mayor resistencia a los antibióticos al superar las defensas del huésped. Debido a que el QS regula múltiples factores de virulencia y a que no regula procesos esenciales, bloquearlo conllevaría a la atenuación de bacterias patógenas sin ejercer presiones selectivas (Tan 2013). El sistema comprende el coordinador transcripcional LasR el cual al ser activado por su molécula autoinductora N-3-oxo-dodecanoil homoserina lactona (3-oxo-C12 HSL) se une a la región promotora del ácido desoxirribonucleico (ADN), regulando la activación de genes causantes de la infección. Es así como este estudio tiene por objetivo la búsqueda e identificación de moléculas como potenciales antagonistas del factor transcripcional LasR. El estudio quimioinformático comprendió un estudio del espacio químico basado en propiedades fisicoquímicas para obtener un perfil de viabilidad respecto a fármacos aprobados a partir del curado de una base de 5514 compuestos únicos. Se utilizaron tres programas de acoplamiento molecular incluyendo un método de puntuación por consenso y un cálculo de huellas digitales de interacción proteína-ligando (PLIF) en la búsqueda de similitud y diversidad en los modos de unión. Fueron seleccionados 12 compuestos para los ensayos de bioactividad con las cepas American Type Culture Collection (ATCC) BAA047 y 27853. Primero, se determinó la concentración en la que no se afectaba el crecimiento bacteriano (12,5 a 200 µg/mL) y posteriormente la cuantificación de la formación de biopelícula por dilución seriada. La prueba de Duncan fue usada para el análisis estadístico. La cepa bioindicadora Chromobacterium violaceum ATCC 12472 se empleó para los ensayos de inhibición del QS. Las moléculas con los mejores resultados antibiopelícula fueron evaluadas por ensayos de expresión génica contra los genes lasR y lasI. Los resultados mostraron la similitud en el espacio químico de los compuestos de la librería con los fármacos aprobados del DrugBank, incluyendo algunas excepciones. Los compuestos candidatos mediante SBVS mostraron un valor de consenso por autoescalado en un rango entre 0,54 y 0,75, superior al del ligando nativo de 0,39. Los ensayos experimentales sugirieron a los compuestos Z2, Z4, Z6, Z9 y Z12 como inhibidores de la formación de biopelícula en concentraciones de 3,1 a 100 µg/mL, y de estos, la flavanona isoglabranina (Z4) y la xantona gamma mangostina (Z9) como inhibidores en la expresión de los genes lasR y lasI. Se demostró que el compuesto Z4 presentó un efecto sobre la expresión de los genes del 61,4 (lasR) y 56,1 % (lasI) en la cepa 27853 y del 32,3 y 10,6 % en la BAA047, respectivamente, que el compuesto (Z9) afectó la expresión del gen lasI (44,7 %) y lasR (48,1 %) únicamente en la cepa 27853 y el (Z12) afectó significativamente la expresión del gen lasR (80,6 %) en la cepa BAA047. Este tipo de estudios permite aproximaciones en la identificación de moléculas inhibidoras de la proteína LasR a partir de extensas librerías de compuestos con la reducción en los tiempos y los costos asociados en su investigación, así como el reporte de compuestos promisorios de origen natural como inhibidores del sistema QS. (Texto tomado de la fuente) |
| publishDate |
2022 |
| dc.date.accessioned.none.fl_str_mv |
2022-07-19T16:22:37Z |
| dc.date.available.none.fl_str_mv |
2022-07-19T16:22:37Z |
| dc.date.issued.none.fl_str_mv |
2022-07-15 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.none.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
Text |
| dc.type.content.none.fl_str_mv |
Text |
| dc.type.redcol.none.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/81710 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/81710 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
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Reconocimiento 4.0 InternacionalAtribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2López Vallejo, Fabián Harveyded3062059fd87d5db691f0ac84dde83Hernández Rodríguez, Patriciacaad35c95dcca716977dead694aa8e6a300López Piñeros, Laura Patricia0ce75dfcf350bc497ca85cb114cc6f2aGrupo de Investigación en Química de Productos Naturales Vegetales Bioactivos (Quipronab)2022-07-19T16:22:37Z2022-07-19T16:22:37Z2022-07-15https://repositorio.unal.edu.co/handle/unal/81710Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/Varios mecanismos están implicados en el desarrollo de la resistencia en cepas de Pseudomonas aeruginosa. Presiones selectivas han promovido numerosas estrategias de supervivencia bacteriana que han favorecido su adaptación a diversos ambientes (Lu et al., 2019, Tacconelli et al., 2018; Zhong et al., 2020). Uno de los mecanismos de interés es el sistema conocido como quorum sensing (QS) por el que las bacterias se comunican a través de moléculas de señalización (Ouyang et al., 2016; Vasavi et al., 2017). Una vez que las bacterias han alcanzado una alta densidad poblacional, éstas controlan la producción de varios factores de virulencia extracelular y la formación de biopelículas proporcionando mayor resistencia a los antibióticos al superar las defensas del huésped. Debido a que el QS regula múltiples factores de virulencia y a que no regula procesos esenciales, bloquearlo conllevaría a la atenuación de bacterias patógenas sin ejercer presiones selectivas (Tan 2013). El sistema comprende el coordinador transcripcional LasR el cual al ser activado por su molécula autoinductora N-3-oxo-dodecanoil homoserina lactona (3-oxo-C12 HSL) se une a la región promotora del ácido desoxirribonucleico (ADN), regulando la activación de genes causantes de la infección. Es así como este estudio tiene por objetivo la búsqueda e identificación de moléculas como potenciales antagonistas del factor transcripcional LasR. El estudio quimioinformático comprendió un estudio del espacio químico basado en propiedades fisicoquímicas para obtener un perfil de viabilidad respecto a fármacos aprobados a partir del curado de una base de 5514 compuestos únicos. Se utilizaron tres programas de acoplamiento molecular incluyendo un método de puntuación por consenso y un cálculo de huellas digitales de interacción proteína-ligando (PLIF) en la búsqueda de similitud y diversidad en los modos de unión. Fueron seleccionados 12 compuestos para los ensayos de bioactividad con las cepas American Type Culture Collection (ATCC) BAA047 y 27853. Primero, se determinó la concentración en la que no se afectaba el crecimiento bacteriano (12,5 a 200 µg/mL) y posteriormente la cuantificación de la formación de biopelícula por dilución seriada. La prueba de Duncan fue usada para el análisis estadístico. La cepa bioindicadora Chromobacterium violaceum ATCC 12472 se empleó para los ensayos de inhibición del QS. Las moléculas con los mejores resultados antibiopelícula fueron evaluadas por ensayos de expresión génica contra los genes lasR y lasI. Los resultados mostraron la similitud en el espacio químico de los compuestos de la librería con los fármacos aprobados del DrugBank, incluyendo algunas excepciones. Los compuestos candidatos mediante SBVS mostraron un valor de consenso por autoescalado en un rango entre 0,54 y 0,75, superior al del ligando nativo de 0,39. Los ensayos experimentales sugirieron a los compuestos Z2, Z4, Z6, Z9 y Z12 como inhibidores de la formación de biopelícula en concentraciones de 3,1 a 100 µg/mL, y de estos, la flavanona isoglabranina (Z4) y la xantona gamma mangostina (Z9) como inhibidores en la expresión de los genes lasR y lasI. Se demostró que el compuesto Z4 presentó un efecto sobre la expresión de los genes del 61,4 (lasR) y 56,1 % (lasI) en la cepa 27853 y del 32,3 y 10,6 % en la BAA047, respectivamente, que el compuesto (Z9) afectó la expresión del gen lasI (44,7 %) y lasR (48,1 %) únicamente en la cepa 27853 y el (Z12) afectó significativamente la expresión del gen lasR (80,6 %) en la cepa BAA047. Este tipo de estudios permite aproximaciones en la identificación de moléculas inhibidoras de la proteína LasR a partir de extensas librerías de compuestos con la reducción en los tiempos y los costos asociados en su investigación, así como el reporte de compuestos promisorios de origen natural como inhibidores del sistema QS. (Texto tomado de la fuente)Several mechanisms are involved in the development of resistance in P. aeruginosa strains. Selective pressures have promoted numerous bacterial survival strategies that have favored their adaptation to diverse environments (Lu et al., 2019, Tacconelli et al., 2018; Zhong et al., 2020). One such mechanism of interest is the system known as quorum sensing (QS) by which bacteria communicate through signaling molecules (Ouyang et al., 2016; Vasavi et al., 2017). Once bacteria have reached a high population density, they control the production of various extracellular virulence factors and biofilm formation providing increased antibiotic resistance by overcoming host defenses. Because the QS regulates multiple virulence factors and does not regulate essential processes, blocking it would lead to attenuation of pathogenic bacteria without exerting selective pressures (Tan 2013). The system comprises the transcriptional coordinator LasR which when activated by its autoinducer molecule N-3-oxo-dodecanoyl homoserine lactone (3-oxo-C12 HSL) binds to the promoter region of deoxyribonucleic acid (DNA), regulating the activation of infection-causing genes. Thus, this study aims to search for and identify molecules as potential antagonists of the transcriptional factor LasR. The chemoinformatics study included a chemical space study based on physicochemical properties to obtain a viability profile with respect to approved drugs from the curation of a base of 5514 compounds. Three molecular docking programs including a consensus scoring method and a protein-ligand interaction fingerprinting (PLIF) calculation were used in the search for similarity and diversity in binding modes. Twelve compounds were selected for bioactivity assays with American Type Culture Collection (ATCC) strains BAA047 and 27853. First, the concentration at which bacterial growth was not affected (12,5 to 200 µg/mL) was determined, followed by quantification of biofilm formation by serial dilution. Duncan's test was used for statistical analysis. The bioindicator strain Chromobacterium violaceum ATCC 12472 was used for QS inhibition assays. The molecules with the best antibiofilm results were evaluated by gene expression assays against lasR and lasI genes. The results showed the similarity in chemical space of the library compounds to the approved drugs from DrugBank, including some exceptions. The candidate compounds by SBVS showed a consensus value by autoscaling in the range of 0,54 to 0,75, higher than that of the native ligand 0,39. Experimental assays suggested compounds Z2, Z4, Z6, Z9 and Z12 as inhibitors of biofilm formation at concentrations from 3,1 to 100 µg/mL and flavanone isoglabranin (Z4) and xanthone gamma mangosteen (Z9) as inhibitors of lasR and lasI gene expression. It was shown that compound Z4 presented an effect on gene expression of 61,4 (lasR) and 56,1 % (lasI) in strain 27853 and 32,3 and 10,6 % in BAA047, respectively and that compound (Z9) affected lasI (44,7 %) and lasR (48,1 %) gene expression only in strain 27853 and (Z12) significantly affected lasR gene expression (80,6 %) in strain BAA047. This type of study allows approaches in the search for molecules that inhibit the LasR protein from extensive libraries of compounds with a reduction in the time and costs associated with their research, as well as the report of promising compounds of natural origin as inhibitors of the QS system.MINCIENCIAS con la beca joven investigador convocatoria 812-2018 y al Macroproyecto con código 11017775815 convocatoria para proyectos de ciencia, tecnología e innovación en salud 2017.MaestríaMagíster en Ciencias - BioquímicaModelamiento molecular (MDML)application/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias - BioquímicaDepartamento de QuímicaFacultad de CienciasUniversidad Nacional de Colombia - Sede Bogotá540 - Química y ciencias afinesPseudomonas aeruginosalasRquorum sensingbiofilmmolecular dockinggene expressionbiopelículaacoplamiento molecularexpresión génicaIdentificación de moléculas inhibidoras en la expresión de lasR como regulador del sistema Quorum Sensing en Pseudomonas aeruginosaIdentification of inhibitory molecules in the expression of lasR as a regulator of the Quorum Sensing in Pseudomonas aeruginosaTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTextTexthttp://purl.org/redcol/resource_type/TM• Ahmed, S. A., Rudden, M., Smyth, T. J., Dooley, J. S., Marchant, R., & Banat, I. M. (2019). Natural quorum sensing inhibitors effectively downregulate gene expression of Pseudomonas aeruginosa virulence factors. Applied microbiology and biotechnology, 103(8), 3521-3535. • Álvarez, C., Cortés, J., Sánchez, R., Castillo, J., Buitrago, G., & Meneses, A. (2010). Resultados del Proyecto: “Impacto Clínico y Económico de la Resistencia Bacteriana en hospitales del Distrito. Boletín Informativo GREBO, (2027), 1–35. • Ansori, A. N. M., Fadholly, A., Hayaza, S., Susilo, R. J. K., Inayatillah, B., Winarni, D., & Husen, S. A. (2020). A review on medicinal properties of mangosteen (Garcinia mangostana L.) Research Journal of Pharmacy and Technology, 13(2), 974-982. • Balasubramanian, et. al. (2013). A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulence. Nucleic Acids Research, 41(1), 1–20. • Borges, A., Abreu, A. C., Dias, C., Saavedra, M. J., Borges, F., & Simões, M. 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Chemistry and Biology, 16(9), 961–970.identificación de moléculas líderes de origen natural con acción multidiana como inhibidores de quorum sensing en Pseudomonas aeruginosa multirresistente.MINCIENCIASEstudiantesInvestigadoresORIGINAL1023899084.2022.pdf1023899084.2022.pdfTesis de Maestría en Ciencias-Bioquímicaapplication/pdf3511199https://repositorio.unal.edu.co/bitstream/unal/81710/1/1023899084.2022.pdf72a256a77389e3ba4c23bb5d3cef96f0MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/81710/2/license.txt8153f7789df02f0a4c9e079953658ab2MD52THUMBNAIL1023899084.2022.pdf.jpg1023899084.2022.pdf.jpgGenerated Thumbnailimage/jpeg5110https://repositorio.unal.edu.co/bitstream/unal/81710/3/1023899084.2022.pdf.jpgc8f4cf6315b05b6fda62eeccdb2008ceMD53unal/81710oai:repositorio.unal.edu.co:unal/817102024-09-19 16:11:08.554Repositorio Institucional Universidad Nacional de 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