Estudio de asociación de genoma completo en aislamientos clínicos de Mycobacterium tuberculosis pan-susceptibles, multi-fármacorresistentes (MDR) y extremadamente resistente (XDR)

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dc.contributor.advisorHurtado Páez, Uriel Alonso
dc.contributor.advisorMoreno Herrera, Claudia Ximena
dc.contributor.authorMosquera Rendón, Jeanneth
dc.date.accessioned2025-09-11T21:38:22Z
dc.date.available2025-09-11T21:38:22Z
dc.date.issued2024
dc.descriptionIlustraciones, gráficosspa
dc.description.abstractEl aumento en los casos de tuberculosis farmacorresistente (TB-DR) en los últimos años, junto con la aparición de aislamientos de Mycobacterium tuberculosis resistentes a nuevos medicamentos como la bedaquilina, y a reutilizados, como la clofazimina, D-cicloserina y linezolid, que representan las últimas alternativas terapéuticas para la TB-DR, resalta la necesidad de comprender los mecanismos que estas bacterias desarrollan para evadir su acción. Este estudio tiene como objetivo principal la implementación de enfoques de estudio de asociación de todo el genoma (GWAS) para identificar variantes genéticas asociadas a diferentes concentraciones inhibitorias mínimas (CIM) a estos medicamentos. Para ello, analizamos 2,056 cepas de M. tuberculosis de diversos países, incluidos 59 de Colombia, integrando datos de secuenciación del genoma completo (WGS) y datos fenotípicos cuantitativos (valores CIM). Los análisis GWAS basados en SNP-INDELS identificaron mutaciones en los genes rplC (Cys154Arg) y Rv0678 (Glu49fs) asociadas con la resistencia a linezolid, bedaquilina y clofazimina. Adicionalmente, los análisis GWAS basados en k-mers revelaron unitigs en los genes aspC, murE, qor, y mmpL5 potencialmente asociadas a diferentes CIM de medicamentos antituberculosos como D-cicloserina y clofazimina. Estos hallazgos demuestran el potencial de los análisis genotipo-fenotipo, combinado con la cuantificación del fenotipo de resistencia a través de las CIM, para detectar variantes genéticas significativas y profundizar nuestra comprensión de los mecanismos de resistencia a los agentes antituberculosos. (Tomado de la fuente)spa
dc.description.abstractThe rise in drug-resistant tuberculosis (DR-TB) cases in recent years, together with the emergence of Mycobacterium tuberculosis isolates resistant to new drugs such as bedaquiline and to repurposed drugs such as clofazimine, D-cycloserine, and linezolid, which represent the latest therapeutic alternatives for DR-TB, highlights the need to understand the mechanisms that these bacteria develop to evade their action. The main aim of this study is to implement genome-wide association study (GWAS) approaches to identify genetic variants associated with different minimum inhibitory concentrations (MICs) to these drugs. To achieve this, we analyzed 2,056 M. tuberculosis strains from various countries, including 59 from Colombia, integrating whole-genome sequencing (WGS) data with quantitative phenotypic measurements (MIC values). SNP-INDELS-based GWAS analyses identified mutations in the rplC (Cys154Arg) and Rv0678 (Glu49fs) genes, which are associated with resistance to linezolid, bedaquiline, and clofazimine. Additionally, Kmers-based GWAS analyses revealed unitigs in the aspC, murE, qor, and mmpL5 genes potentially associated with different MICs of anti-TB drugs such as D-cycloserine and clofazimine. These findings demonstrate the potential of genotype-phenotype analyses, combined with the measurement of resistance phenotypes through MICs, to detect significant genetic variants and deepen our understanding of resistance mechanisms to anti-TB agents.eng
dc.description.curricularareaBiotecnología.Sede Medellín
dc.description.degreelevelDoctorado
dc.description.degreenameDoctor en Biotecnología
dc.format.extent175 páginas
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/88729
dc.language.isospa
dc.publisherUniversidad Nacional de Colombia
dc.publisher.branchUniversidad Nacional de Colombia - Sede Medellín
dc.publisher.facultyFacultad de Ciencias
dc.publisher.placeMedellín, Colombia
dc.publisher.programMedellín - Ciencias - Doctorado en Biotecnología
dc.relation.indexedLaReferencia
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseAtribución-NoComercial 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subject.ddc610 - Medicina y salud::616 - Enfermedades
dc.subject.ddc610 - Medicina y salud::615 - Farmacología y terapéutica
dc.subject.lembTuberculosis - Tratamiento
dc.subject.lembMycobacterium tuberculosis
dc.subject.lembResistencia a las drogas
dc.subject.proposalMycobacterium tuberculosisspa
dc.subject.proposalresistencia antimicrobianaspa
dc.subject.proposalGWASspa
dc.subject.proposalbedaquilinaspa
dc.subject.proposallinezolidspa
dc.subject.proposalclofaziminaspa
dc.subject.proposalD-cicloserinaspa
dc.subject.proposalMycobacterium tuberculosiseng
dc.subject.proposalAntimicrobial resistanceeng
dc.subject.proposalGWASeng
dc.subject.proposalBedaquilineeng
dc.subject.proposalLinezolideng
dc.subject.proposalClofazimineeng
dc.subject.proposalD-cycloserineeng
dc.titleEstudio de asociación de genoma completo en aislamientos clínicos de Mycobacterium tuberculosis pan-susceptibles, multi-fármacorresistentes (MDR) y extremadamente resistente (XDR)spa
dc.title.translatedGenome-wide association study in clinical isolates of pan-susceptible, multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosiseng
dc.typeTrabajo de grado - Doctorado
dc.type.coarhttp://purl.org/coar/resource_type/c_db06
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
dc.type.driverinfo:eu-repo/semantics/doctoralThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TD
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentEstudiantes
dcterms.audience.professionaldevelopmentInvestigadores
dcterms.audience.professionaldevelopmentMaestros
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2

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