Hypermutation in Burkholderia cepacia complex is mediated by DNAmismatch repair inactivation and is highly prevalent in cystic fibrosischronic respiratory infection

PABLO MARTINA; SOFIA FELIZIANI; CARLOS JUAN; MARISA BETTIOL; BLANCA GATTI; OSVALDO YANTORNO; ANDREA SMANIA; ANTONIO OLIVER; ALEJANDRA BOSCH

INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY (PRINT)

ELSEVIER GMBH

Año: 2014 vol. 304 p. 1182 - 1191

1438-4221

The Burkholderia cepacia complex (Bcc) represents an important group of pathogens involved in long-termlung infection in cystic fibrosis (CF) patients. A positive selection of hypermutators, linked to antimicro-bial resistance development, has been previously reported for Pseudomonas aeruginosa in this chronicinfection 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 15environmental samples were analyzed. In order to determine the prevalence of mutators their spon-taneous mutation rates to rifampicin resistance were determined. In addition, the genetic basis of themutator phenotypes was investigated by sequencing the mutS and mutL genes, the main components ofthe mismatch repair system (MRS). The overall prevalence of hypermutators in the collection analyzedwas 13.6%, with highest occurrence (40.7%) among the chronically infected CF patients, belonging mainlyto B. cenocepacia, B. multivorans, B. cepacia, and B. contaminans ? the most frequently recovered Bcc speciesfrom 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, theresistance-profiles to 17 antimicrobial agents was evaluated. High antimicrobial resistance rates weredocumented for all the Bcc species recovered from CF patients, but, except for ciprofloxacin, a significantassociation with hypermutation was not detected. In conclusion, in the present study we demonstratefor the first time that, MRS-deficient Bcc species mutators are highly prevalent and positively selected inCF chronic lung infections. Hypermutation therefore, might be playing a key role in increasing bacterialadaptability to the CF-airway environment, facilitating the persistence of chronic lung infections