Abstract
Achromobacter xylosoxidans has attracted increasing attention as an emerging pathogen in patients with cystic fibrosis. Intrinsic resistance to several classes of antimicrobials and the ability to form robust biofilms in vivo contribute to the clinical manifestations of persistent A. xylosoxidans infection. Still, much of A. xylosoxidans biofilm formation remains uncharacterized due to the scarcity of existing genetic tools. Here we demonstrate a promising genetic system for use in A. xylosoxidans; generating a transposon mutant library which was then used to identify genes involved in biofilm development in vitro. We further described the effects of one of the genes found in the mutagenesis screen, encoding a putative enoyl-CoA hydratase, on biofilm structure and tolerance to antimicrobials. Through additional analysis, we find that a fatty acid signaling compound is essential to A. xylosoxidans biofilm ultrastructure and maintenance. This work describes methods for the genetic manipulation of A. xylosoxidans and demonstrated their use to improve our understanding of A. xylosoxidans pathophysiology.
Highlights
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein that resides at the apical surface of many epithelial cell types
The prevalence of A. xylosoxidans is estimated to be as high as 20% among individuals with CF,[6,7,8,9,10,11] which is of increasing concern given its reported correlation to lung function decline,[3] patient-to-patient transmissibility,[5] and multi-drug resistance phenotypes.[12,13,14,15]
This study is an important step in that direction as it identifies several molecular determinants of biofilm growth, thought to play a critical role in the persistence and pathogenesis of A. xylosoxidans in the CF airways.[16]
Summary
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein that resides at the apical surface of many epithelial cell types. CFTR defects result in abnormal chloride and bicarbonate transport, increasing mucus viscosity in the pancreas, paranasal sinuses, digestive tract, and most notably, the lower airways. Many other multidrug-resistant opportunistic bacterial species have received attention for their association with CF disease progression.[2]. Achromobacter xylosoxidans is notable given its association with poor pulmonary function scores and apparent patient-to-patient transmissibility.[3,4,5] This aerobic, Gram-negative opportunistic pathogen has been found to colonize anywhere from 2 to 20 percent of CF subjects, though its prevalence has risen in recent years,[4,6,7,8,9,10,11] sparking a renewed interest in its pathophysiology. Of particular concern is the intrinsic and acquired resistance of A. xlyosoxidans to multiple classes of antimicrobial agents, including aminoglycosides, beta-lactams, carbapenems, chloramphenicol and fluoroquinolones, which presents a significant burden for infection control.[7,8,12,13,14,15]
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