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Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans.

ABSTRACT: Achromobacter xylosoxidans is an opportunistic pathogen known to be resistant to a wide range of antibiotics; however, the knowledge about the drug resistance mechanisms is limited. We used a high-throughput sequencing approach to sequence the genomes of the A. xylosoxidans type strain ATCC 27061 and a clinical isolate, A. xylosoxidans X02736, and then we used different bioinformatics tools to analyze the drug resistance genes in these bacteria. We obtained the complete genome sequence for A. xylosoxidans ATCC 27061 and the draft sequence for X02736. We predicted a total of 50 drug resistance-associated genes in the type strain, including 5 genes for ?-lactamases and 17 genes for efflux pump systems; these genes are also conserved among other A. xylosoxidans genomes. In the clinical isolate, except for the conserved resistance genes, we also identified several acquired resistance genes carried by a new transposon embedded in a novel integrative and conjugative element. Our study provides new insights into the intrinsic and acquired drug resistance mechanisms in A. xylosoxidans, which will be helpful for better understanding the physiology of A. xylosoxidans and the evolution of antibiotic resistance in this bacterium.

SUBMITTER: Hu Y

PROVIDER: S-EPMC4335856 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans.

Hu Yongfei Y Zhu Yuying Y Ma Yanan Y Liu Fei F Lu Na N Yang Xi X Luan Chunguang C Yi Yong Y Zhu Baoli B

Antimicrobial agents and chemotherapy 20141208 2

Achromobacter xylosoxidans is an opportunistic pathogen known to be resistant to a wide range of antibiotics; however, the knowledge about the drug resistance mechanisms is limited. We used a high-throughput sequencing approach to sequence the genomes of the A. xylosoxidans type strain ATCC 27061 and a clinical isolate, A. xylosoxidans X02736, and then we used different bioinformatics tools to analyze the drug resistance genes in these bacteria. We obtained the complete genome sequence for A. xy ...[more]

PMID: 25487802

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Project description:Achromobacter denitrificans is an environmental opportunistic pathogen that is infecting a large number of immunocompromised patients. A more recently identified strain from the historical collection of strains of Achromobacter denitrificans is Achromobacter mucicolens. In hosts with a variety of underlying diseases, Achromobacter spp. can induce a wide spectrum of disorders. Because of the bacterium's intrinsic genetic constitution and resistance gained over time, antibiotics are challenged to handle A. mucicolens. Due to the fact that A. mucicolens is rare and its taxonomy is not completely understood, it is difficult to define clinical symptoms, acquisition risk factors, and thus the best therapeutic course of action. To help comprehend this intrinsic and acquired resistance, we analyzed the entire genome of the A. mucicolens IA strain and utilized bioinformatics methods to estimate the strain's probable drug resistance profile. In our study, we have isolated and cultured a clinically important A. mucicolens strain and subjected it to antimicrobial susceptibility tests against antibiotics in the Vitek 2 testing system. The strain's genome sequence as well as an investigation of 27 of its phenotypic traits provides important information regarding this pathogen. The genome of this A. mucicolens IA strain possesses a number of antibiotic resistance genes that code for efflux pump systems and other antibiotic-regulating as well as -modifying enzymes. Our research analysis predicted genes involved in drug resistance, including genes for efflux pump systems, antibiotic efflux, antibiotic inactivation, and antibiotic target alteration. In vitro studies validated the genomic evidence for its ability to exhibit resistance against a wide range of antibiotics. Our investigation paves the way for more research on understanding the functioning of the key discovered genes that contribute toward the pathogenicity of A. mucicolens and hence gives new information and treatment options for this emerging pathogen. IMPORTANCE Achromobacter species are well-known opportunistic human pathogens that can be found in water and soil and most commonly in hospital settings. They thrive in immunocompromised individuals, producing sporadic cases of pneumonia, septicemia, peritonitis, urinary tract infections, and other illnesses. Achromobacter strains are inherently resistant to a wide spectrum of antibiotics, making them difficult to treat promptly. The strain under study, A. mucicolens, was notably resistant to various antibiotics, and the infection could be controlled only after several rounds of prescription medications at different doses. This consumed a lot of time and put the already immunosuppressed leukemic patient through a great ordeal. The study aimed to raise awareness about the importance of the Achromobacter bacterium's lethality, and doctors should evaluate the bacterium's potential for resistance before prescribing antibiotics. Sanitation and other precautions should also be implemented in hospitals and other public places.

Project description:Bacterial pathogens evolve during chronic colonization of the human host by selection for pathoadaptive mutations. One of the emerging and understudied bacterial species causing chronic airway infections in patients with cystic fibrosis (CF) is Achromobacter xylosoxidans. It can establish chronic infections in patients with CF, but the genetic and phenotypic changes associated with adaptation during these infections are not completely understood. In this study, we analyzed the whole-genome sequences of 55 clinical A. xylosoxidans isolates longitudinally collected from the sputum of 6 patients with CF. Four genes encoding regulatory proteins and two intergenic regions showed convergent evolution, likely driven by positive selection for pathoadaptive mutations, across the different clones of A. xylosoxidans. Most of the evolved isolates had lower swimming motility and were resistant to multiple classes of antibiotics, while fewer of the evolved isolates had slower growth or higher biofilm production than the first isolates. Using a genome-wide association study method, we identified several putative genetic determinants of biofilm formation, motility and β-lactam resistance in this pathogen. With respect to antibiotic resistance, we discovered that a combination of mutations in pathoadaptive genes (phoQ and bigR) and two other genes encoding regulatory proteins (spoT and cpxA) were associated with increased resistance to meropenem and ceftazidime. Altogether, our results suggest that genetic changes within regulatory loci facilitate within-host adaptation of A. xylosoxidans and the emergence of adaptive phenotypes, such as antibiotic resistance or biofilm formation. IMPORTANCE A thorough understanding of bacterial pathogen adaptation is essential for the treatment of chronic bacterial infections. One unique challenge in the analysis and interpretation of genomics data is identifying the functional impact of mutations accumulated in the bacterial genome during colonization in the human host. Here, we investigated the genomic and phenotypic evolution of A. xylosoxidans in chronic airway infections of patients with CF and identified several mutations associated with the phenotypic evolution of this pathogen using genome-wide associations. Identification of phenotypes under positive selection and the associated mutations can enlighten the adaptive processes of this emerging pathogen in human infections and pave the way for novel therapeutic interventions.

Dataset Information

Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans.

Publications

Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans.

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