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dc.creatorMolina Mora, José Arturo
dc.creatorChinchilla Montero, Diana
dc.creatorChavarría Azofeifa, Maribel
dc.creatorUlloa Morales, Alejandro J.
dc.creatorCampos Sánchez, Rebeca
dc.creatorMora Rodríguez, Rodrigo Antonio
dc.creatorShi, Leming
dc.creatorGarcía Santamaría, Fernando
dc.date.accessioned2020-12-15T15:33:28Z
dc.date.available2020-12-15T15:33:28Z
dc.date.issued2020
dc.identifier.citationhttps://www.nature.com/articles/s41598-020-70581-2
dc.identifier.urihttps://hdl.handle.net/10669/82204
dc.description.abstractPseudomonas aeruginosa is an opportunistic pathogen that thrives in diverse environments and causes a variety of human infections. Pseudomonas aeruginosa AG1 (PaeAG1) is a high-risk sequence type 111 (ST-111) strain isolated from a Costa Rican hospital in 2010. PaeAG1 has both blaVIM-2 and blaIMP-18 genes encoding for metallo-β-lactamases, and it is resistant to β-lactams (including carbapenems), aminoglycosides, and fluoroquinolones. Ciprofloxacin (CIP) is an antibiotic commonly used to treat P. aeruginosa infections, and it is known to produce DNA damage, triggering a complex molecular response. In order to evaluate the effects of a sub-inhibitory CIP concentration on PaeAG1, growth curves using increasing CIP concentrations were compared. We then measured gene expression using RNA-Seq at three time points (0, 2.5 and 5 h) after CIP exposure to identify the transcriptomic determinants of the response (i.e. hub genes, gene clusters and enriched pathways). Changes in expression were determined using differential expression analysis and network analysis using a top–down systems biology approach. A hybrid model using database-based and co-expression analysis approaches was implemented to predict gene–gene interactions. We observed a reduction of the growth curve rate as the sub-inhibitory CIP concentrations were increased. In the transcriptomic analysis, we detected that over time CIP treatment resulted in the differential expression of 518 genes, showing a complex impact at the molecular level. The transcriptomic determinants were 14 hub genes, multiple gene clusters at different levels (associated to hub genes or as co-expression modules) and 15 enriched pathways. Down-regulation of genes implicated in several metabolism pathways, virulence elements and ribosomal activity was observed. In contrast, amino acid catabolism, RpoS factor, proteases, and phenazines genes were up-regulated. Remarkably, > 80 resident-phage genes were up-regulated after CIP treatment, which was validated at phenomic level using a phage plaque assay. Thus, reduction of the growth curve rate and increasing phage induction was evidenced as the CIP concentrations were increased. In summary, transcriptomic and network analyses, as well as the growth curves and phage plaque assays provide evidence that PaeAG1 presents a complex, concentration-dependent response to sub-inhibitory CIP exposure, showing pleiotropic effects at the systems level. Manipulation of these determinants, such as phage genes, could be used to gain more insights about the regulation of responses in PaeAG1 as well as the identification of possible therapeutic targets. To our knowledge, this is the first report of the transcriptomic analysis of CIP response in a ST-111 high-risk P. aeruginosa strain, in particular using a top-down systems biology approach.es_ES
dc.language.isoen_USes_ES
dc.sourceScientific Reports volume 10, Article number: 13717 (2020)es_ES
dc.subjectAntimicrobialses_ES
dc.subjectBacteriaes_ES
dc.subjectBacteriologyes_ES
dc.subjectBacteriophageses_ES
dc.subjectCellular signalling networkses_ES
dc.subjectData processinges_ES
dc.subjectGene regulatory networkses_ES
dc.subjectMicrobial geneticses_ES
dc.subjectNetwork topologyes_ES
dc.subjectSystems biologyes_ES
dc.titleTranscriptomic determinants of the response of ST-111 Pseudomonas aeruginosa AG1 to ciprofloxacin identified by a top-down systems biology approaches_ES
dc.typeartículo original
dc.identifier.doihttps://doi.org/10.1038/s41598-020-70581-2
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)es_ES
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)es_ES
dc.description.procedenceUCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologíaes_ES


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