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dc.contributor.authorCebrián-Sastre, E
dc.contributor.authorChiner-Oms, A
dc.contributor.authorTorres-Pérez, R
dc.contributor.authorComas, I
dc.contributor.authorOliveros, J C
dc.contributor.authorBlázquez, J
dc.contributor.authorCastañeda-García, Alfredo
dc.identifier.citationMicrobiol Spectr. 2023 Aug 17;11(4):e0101723.es_ES
dc.description.abstractResistance to the frontline antibiotic rifampicin constitutes a challenge to the treatment and control of tuberculosis. Here, we analyzed the mutational landscape of Mycobacterium smegmatis during long-term evolution with increasing concentrations of rifampicin, using a mutation accumulation assay combined with whole-genome sequencing. Antibiotic treatment enhanced the acquisition of mutations, doubling the genome-wide mutation rate of the wild-type cells. While antibiotic exposure led to extinction of almost all wild-type lines, the hypermutable phenotype of the ΔnucS mutant strain (noncanonical mismatch repair deficient) provided an efficient response to the antibiotic, leading to high rates of survival. This adaptative advantage resulted in the emergence of higher levels of rifampicin resistance, an accelerated acquisition of drug resistance mutations in rpoB (β RNA polymerase), and a wider diversity of evolutionary pathways that led to drug resistance. Finally, this approach revealed a subset of adaptive genes under positive selection with rifampicin that could be associated with the development of antibiotic resistance. IMPORTANCE Rifampicin is the most important first-line antibiotic against mycobacterial infections, including tuberculosis, one of the top causes of death worldwide. Acquisition of rifampicin resistance constitutes a major global public health problem that makes the control of the disease challenging. Here, we performed an experimental evolution assay under antibiotic selection to analyze the response and adaptation of mycobacteria, leading to the acquisition of rifampicin resistance. This approach explored the total number of mutations that arose in the mycobacterial genomes under long-term rifampicin exposure, using whole-genome sequencing. Our results revealed the effect of rifampicin at a genomic level, identifying different mechanisms and multiple pathways leading to rifampicin resistance in mycobacteria. Moreover, this study detected that an increase in the rate of mutations led to enhanced levels of drug resistance and survival. In summary, all of these results could be useful to understand and prevent the emergence of drug-resistant isolates in mycobacterial infections.es_ES
dc.description.sponsorshipThis research was funded by MCIN/AEI/10.13039/501100011033, grant PID2020-112865RB-I00, and Instituto de Salud Carlos III, grant FIS PI17/00159 (ISCIII/FEDER, UE). E.C.-S. is the recipient of a PFIS predoctoral research fellowship (FI18/00036) cofinanced by the Instituto de Salud Carlos III and the European Social Fund. A.C.-G. acknowledges financial support from the Spanish State Research Agency, AEI/10.13039/501100011033, through the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0347, SEV-2017-0712). Editorial assistance was provided by Stuart L. Rulten. Statistical consultancy was provided by Applied Statistical Department-SGAI-CSIC.es_ES
dc.publisherAmerican Society for Microbiology (ASM) es_ES
dc.subjectDNA repaires_ES
dc.subjectMycobacterium smegmatises_ES
dc.subjectAntibiotic resistancees_ES
dc.subjectDrug resistance evolutiones_ES
dc.subjectExperimental evolutiones_ES
dc.subjectMutation accumulationes_ES
dc.titleSelective Pressure by Rifampicin Modulates Mutation Rates and Evolutionary Trajectories of Mycobacterial Genomeses_ES
dc.typeresearch articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderAgencia Estatal de Investigación (España) es_ES
dc.contributor.funderInstituto de Salud Carlos III es_ES
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) es_ES
dc.contributor.funderMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) es_ES
dc.identifier.journalMicrobiology spectrumes_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/MINECO//SEV-2013-0347/ES/-/ es_ES
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/Subprograma Estatal de Generación de Conocimiento/PI17 - Proyectos de investigacion en salud (AES 2017). Modalidad proyectos en salud. (2017)/PI17/00159es_ES
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/null/Contratos Predoctorales de Formación en investigación en salud (PFIS) (2018)/FI18/00036es_ES

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