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Bacterial persisters in long-term infection: Emergence and fitness in a complex host environment

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  1. In vitro adaptation and characterization of attenuated hypervariable region 1 swap chimeras of hepatitis C virus

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  2. Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria

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  3. Equine pegiviruses cause persistent infection of bone marrow and are not associated with hepatitis

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  4. Hypermutation as an Evolutionary Mechanism for Achromobacter xylosoxidans in Cystic Fibrosis Lung Infection

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  5. The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus

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  1. Correlates of Pancreatic Enzyme Replacement Therapy Intake in Adults with Cystic Fibrosis: Results of a Cross-Sectional Study

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  2. Diagnostic criteria of CNS infection in patients with external ventricular drainage after traumatic brain injury: a pilot study

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  3. Achromobacter spp. in a Cohort of Non-Selected Pre-and Post-Lung Transplant Recipients

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  4. A retrospective review of Achromobacter species and antibiotic treatments in patients with primary ciliary dyskinesia

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Despite intensive antibiotic treatment, Pseudomonas aeruginosa often persists in the airways of cystic fibrosis (CF) patients for decades, and can do so without antibiotic resistance development. Using high-throughput screening assays of bacterial survival after treatment with high concentrations of ciprofloxacin, we have determined the prevalence of persisters in a large patient cohort using 460 longitudinal isolates of P. aeruginosa from 39 CF patients. Isolates were classed as high persister variants (Hip) if they regrew following antibiotic treatment in at least 75% of the experimental replicates. Strain genomic data, isolate phenotyping, and patient treatment records were integrated in a lineage-based analysis of persister formation and clinical impact. In total, 19% of the isolates were classified as Hip and Hip emergence increased over lineage colonization time within 22 Hip+ patients. Most Hip+ lineages produced multiple Hip isolates, but few Hip+ lineages were dominated by Hip. While we observed no strong signal of adaptive genetic convergence within Hip isolates, they generally emerged in parallel or following the development of ciprofloxacin resistance and slowed growth. Transient lineages were majority Hip-, while strains that persisted over a clinically diagnosed 'eradication' period were majority Hip+. Patients received indistinguishable treatment regimens before Hip emergence, but Hip+ patients overall were treated significantly more than Hip- patients, signaling repeated treatment failure. When subjected to in vivo-similar antibiotic dosing, a Hip isolate survived better than a non-Hip in a structured biofilm environment. In sum, the Hip phenotype appears to substantially contribute to long-term establishment of a lineage in the CF lung environment. Our results argue against the existence of a single dominant molecular mechanism underlying bacterial antibiotic persistence. We instead show that many routes, both phenotypic and genetic, are available for persister formation and consequent increases in strain fitness and treatment failure in CF airways.

Original languageEnglish
JournalPLoS pathogens
Volume16
Issue number12
Pages (from-to)e1009112
ISSN1553-7366
DOIs
Publication statusPublished - Dec 2020

    Research areas

  • Adult, Cystic Fibrosis/microbiology, Female, Genetic Fitness, Host-Pathogen Interactions/physiology, Humans, Male, Pseudomonas Infections/genetics, Pseudomonas aeruginosa/genetics

ID: 61993229