Achromobactergenetic adaptation in cystic fibrosis

Abstract

Achromobacter is an emerging pathogen in patients with cystic fibrosis (CF) and Achromobacter caused infections are associated with more severe disease outcomes and high intrinsic antibiotic resistance. While conventional CF pathogens are studied extensively, little is known about the genetic determinants leading to antibiotic resistance and the genetic adaptation in Achromobacter infections.Here, we analyzed 101 Achromobacter genomes from 51 patients with CF isolated during the course of up to 20 years of infection to identify within-host adaptation, mutational signatures, and genetic variation associated with increased antibiotic resistance.We found that the same regulatory and inorganic ion transport genes were frequently mutated in persisting clone types within and between Achromobacter species indicating convergent genetic adaptation. Genome-wide association study (GWAS) of six antibiotic resistance phenotypes revealed the enrichment of associated genes involved in inorganic ion transport genes, transcription gene enrichment in β-lactams, and energy production and translation gene enrichment in the trimethoprim/sulfonamide group.Overall, we provide insights into the pathogenomics of Achromobacter infections in patients with CF airways. Since emerging pathogens are increasingly recognised as an important healthcare issue, our findings on evolution of antibiotic resistance and genetic adaptation can facilitate better understanding of disease progression and how mutational changes have implications for patients with CF.

Genomic and Phenotypic Evolution of Achromobacter xylosoxidans during Chronic Airway Infections of Patients with Cystic Fibrosis

“…The overall average substitution rate for all clones excluding the hypermutator CF1 was 2.7 SNPs/year ( Fig. 2B ), which is close to the previously reported 1.9 SNPs/year in CF adapted isolates of A. xylosoxidans genomes ( 24 ). In comparison, the mean substitution rates of CF adapted genomes of P. aeruginosa and B. multivorans were reported at 2.6 and 2.4 SNPs/year, respectively ( 22 , 25 ).…”

“…The fourth pathoadaptive gene encoded a putative HAMP domain histidine kinase PhoQ, which is associated with virulence, motility, and polymyxin resistance in Salmonella enterica serovar Typhimurium and P. aeruginosa ( 29 – 31 ). With the exception of hrcA , all other genes were found to be pathoadaptive in CF-adapted A. xylosoxidans from another study, confirming the relevance of these loci in genetic adaptation of A. xylosoxidans in CF ( 24 ). Moreover, the two intergenic loci had mutations upstream of genes encoding the septum formation protein Maf and a TonB siderophore receptor, which may be involved in metal uptake through siderophores similar to metal uptake in P. aeruginosa ( 32 , 33 ).…”

“…Infections of A. xylosoxidans have recently become more prevalent in patients with CF ( 5 , 6 , 9 ), but there are few studies that characterize the genetic adaptation of Achromobacter spp. in CF infections ( 24 , 48 , 49 ). To complement these studies, we used a combination of functional and genomic approaches to reflect on the biology of A. xylosoxidans adaptation in the CF model.…”

Role of RND Efflux Pumps in Drug Resistance of Cystic Fibrosis Pathogens

“…Only three of these efflux systems have been fully characterized so far, showing the ability to confer resistance to CF used drugs, such as fluoroquinolones andtrimethoprim/sulfamethoxazole (Supplementary Table S1). As an example, Gabrielaite and collaborators [160], performing a genomic analysis on 101 clinical strains isolated within a time span of 20 years in a Denmark CF center, found that in 38% of the analyzed lineages mutations in the gene axyZ (axyXY-oprZ transcriptional repressor) were present. The presence of axyZ mutations led to an overall increase of tolerance to antibiotics since AxyXY-OprZ has a broad spectrum of activity.…”

“…This demonstrates that AxyZ is involved in a wide regulatory pathway controlling the activation of disparate AR mechanisms. The AxyZ mutations can be quite easily selected in vitro by exposure of the bacterium to aminoglycosides [158], a class of antibiotic extensively used for CF infections treatment, and consequently these are reported to be frequently associated with the pathoadaptive process of A. xylosoxidans, A. ruhlandii and A. insuavis in CF lung [160].…”