Martina Pablo, Feliziani Sofía, Juan Carlos, Bettiol Marisa, Gatti Blanca, Yantorno Osvaldo, Smania Andrea M, Oliver Antonio, Bosch Alejandra
CINDEFI-CONICET-CCT La Plata, Centro de Biotecnología Aplicada, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
CIQUIBIC-CONICET, Centro de Investigaciones en Química Biológica de Córdoba, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina.
Int J Med Microbiol. 2014 Nov;304(8):1182-91. doi: 10.1016/j.ijmm.2014.08.011. Epub 2014 Aug 28.
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.
洋葱伯克霍尔德菌复合体（Bcc）是一类重要的病原体，与囊性纤维化（CF）患者的长期肺部感染有关。先前已有报道，在这种慢性感染环境中，铜绿假单胞菌存在与抗菌药物耐药性发展相关的超突变体的正向选择。然而，Bcc菌种中的超突变能力尚未得到系统评估。我们分析了从48例CF患者、10例非CF患者和15份环境样本中分离出的125株特征明确的Bcc菌株。为了确定超突变体的流行率，测定了它们对利福平耐药的自发突变率。此外，通过对错配修复系统（MRS）的主要组成部分mutS和mutL基因进行测序，研究了超突变体表型的遗传基础。在所分析的菌株集合中，超突变体的总体流行率为13.6%，在慢性感染的CF患者中发生率最高（40.7%），主要属于洋葱伯克霍尔德菌、多食伯克霍尔德菌、洋葱伯克霍尔德菌和污染伯克霍尔德菌——全球CF患者中最常分离到的Bcc菌种。13株（76.5%）超突变体的mutS和/或mutL存在缺陷。最后，为了寻找抗菌药物耐药性与超突变能力之间可能的关联，评估了这些菌株对17种抗菌药物的耐药谱。从CF患者中分离出的所有Bcc菌种均显示出较高的抗菌药物耐药率，但除环丙沙星外，未检测到与超突变有显著关联。总之，在本研究中，我们首次证明，MRS缺陷的Bcc菌种超突变体在CF慢性肺部感染中高度流行且受到正向选择。因此，超突变可能在增强细菌对CF气道环境的适应性、促进慢性肺部感染的持续存在方面发挥关键作用。
