title: PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa.
abstract: Adaptive evolution depends on both the genetic variability in a population of organisms and the selection of the better adapted genotypes. However, for the fittest variants to be selected they must survive over a sufficient period under the new conditions. Bacteria are often exposed to different types of stress in nature, including antibiotics. We analysed the global expression profiles of the opportunistic pathogen Pseudomonas aeruginosa in response to ceftazidime, a PBP3 inhibitor, at different concentrations and times. PBP3 inhibition exerts a global impact on the transcription of a large number of genes. From an adaptive perspective, it is noteworthy the induction of several SOS genes, as well as adaptation, protection and antibiotic resistance genes. Intriguingly, transcription of pyocin genes, previously described as SOS-regulated, was repressed upon PBP3 inhibition. Ciprofloxacin, an SOS inducer, produced transcriptional induction of pyocins. Our results indicate that: (i) the SOS responses resulting from treatments with these two antibiotics cause only partially overlapping transcription profiles; (ii) PBP3 and DNA-gyrase inhibition produce opposite effects on transcription of pyocin genes. Consequently, ceftazidime decreases ciprofloxacin toxicity; (iii) error-prone DNA-polymerase DinB is induced by PBP3 inhibition but not by DNA-gyrase inhibition; (iv) PBP3 inhibition causes induced mutagenesis; (v) ceftazidime upregulates several antibiotic-resistance and adaptation genes; and (vi) ceftazidime concentrations thought previously to be lethal are not, as most cells treated with ceftazidime remain alive and recover their capacity to form colonies. Thus, transcriptional changes demonstrated in this work are likely to be adaptively relevant to cells that survive.
authors.affiliation: Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC). C/Darwin, 3, Campus de la Universidad Autónoma-Cantoblanco, 28049-Madrid, Spain. blazquez@cnb.uam.es
authors.forename: Jesús
authors.initials: J
authors.lastname: Blázquez
authors.forename: José-María
authors.initials: JM
authors.lastname: Gómez-Gómez
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.forename: Carlos
authors.initials: C
authors.lastname: Juan
authors.forename: Vivek
authors.initials: V
authors.lastname: Kapur
authors.forename: Soledad
authors.initials: S
authors.lastname: Martín
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D002442:Ceftazidime / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics; D027081:DNA Gyrase / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D005798:Genes, Bacterial / Q000235:genetics; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011709:Pyocins / Q000378:metabolism; D013014:SOS Response, Genetics / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D011709:Pyocins; D002939:Ciprofloxacin; D002442:Ceftazidime; D027081:DNA Gyrase