title: Hypermutation in Burkholderia cepacia complex is mediated by DNA mismatch repair inactivation and is highly prevalent in cystic fibrosis chronic respiratory infection.
abstract: The Burkholderia cepacia complex (Bcc) represents an important group of pathogens involved in long-term lung infection in cystic fibrosis (CF) patients. A positive selection of hypermutators, linked to antimicrobial resistance development, has been previously reported for Pseudomonas aeruginosa in this chronic infection setting. Hypermutability, however, has not yet been systematically evaluated in Bcc species. A total of 125 well characterized Bcc isolates recovered from 48 CF patients, 10 non-CF patients and 15 environmental samples were analyzed. In order to determine the prevalence of mutators their spontaneous mutation rates to rifampicin resistance were determined. In addition, the genetic basis of the mutator phenotypes was investigated by sequencing the mutS and mutL genes, the main components of the mismatch repair system (MRS). The overall prevalence of hypermutators in the collection analyzed was 13.6%, with highest occurrence (40.7%) among the chronically infected CF patients, belonging mainly to B. cenocepacia, B. multivorans, B. cepacia, and B. contaminans -the most frequently recovered Bcc species from CF patients worldwide. Thirteen (76.5%) of the hypermutators were defective in mutS and/or mutL. Finally, searching for a possible association between antimicrobial resistance and hypermutability, the resistance-profiles to 17 antimicrobial agents was evaluated. High antimicrobial resistance rates were documented for all the Bcc species recovered from CF patients, but, except for ciprofloxacin, a significant association with hypermutation was not detected. In conclusion, in the present study we demonstrate for the first time that, MRS-deficient Bcc species mutators are highly prevalent and positively selected in CF chronic lung infections. Hypermutation therefore, might be playing a key role in increasing bacterial adaptability to the CF-airway environment, facilitating the persistence of chronic lung infections.
authors.affiliation: CINDEFI-CONICET-CCT La Plata, Centro de Biotecnología Aplicada, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martina
authors.affiliation: CIQUIBIC-CONICET, Centro de Investigaciones en Química Biológica de Córdoba, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina.
authors.forename: Sofía
authors.initials: S
authors.lastname: Feliziani
authors.affiliation: Servicio de Microbiología y Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Juan
authors.affiliation: Sala de Microbiología, Hospital de Niños de La Plata "Sor María Ludovica", 1900 La Plata, Argentina.
authors.forename: Marisa
authors.initials: M
authors.lastname: Bettiol
authors.affiliation: Sala de Microbiología, Hospital de Niños de La Plata "Sor María Ludovica", 1900 La Plata, Argentina.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gatti
authors.affiliation: CINDEFI-CONICET-CCT La Plata, Centro de Biotecnología Aplicada, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Yantorno
authors.affiliation: CIQUIBIC-CONICET, Centro de Investigaciones en Química Biológica de Córdoba, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Smania
authors.affiliation: Servicio de Microbiología y Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), 07010 Palma de Mallorca, Spain. Electronic address: antonio.oliver@ssib.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.affiliation: CINDEFI-CONICET-CCT La Plata, Centro de Biotecnología Aplicada, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata, Argentina. Electronic address: bosch@quimica.unlp.edu.ar.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bosch
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019121:Burkholderia Infections / Q000382:microbiology*; D042602:Burkholderia cepacia complex / Q000235:genetics* / Q000302:isolation & purification; D002908:Chronic Disease; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000150:complications*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004783:Environmental Microbiology; D006801:Humans; D008969:Molecular Sequence Data; D059645:Mutation Rate; D012141:Respiratory Tract Infections / Q000382:microbiology*; D012293:Rifampin / Q000494:pharmacology; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D045643:DNA Repair Enzymes; D012293:Rifampin
keywords: Antibiotic resistance; Burkholderia cepacia complex; Chronic infection; Cystic fibrosis; Hypermutation; Mismatch repair system