Laura J Sherrard1, Bryan A Wee2, Christine Duplancic1, Kay A Ramsay3, Keyur A Dave1, Emma Ballard1, Claire E Wainwright4, Keith Grimwood5, Hanna E Sidjabat6, David M Whiley7, Scott A Beatson8, Timothy J Kidd9, Scott C Bell10. 1. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 2. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia. 3. QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia. 4. Faculty of Medicine, The University of Queensland, Brisbane, Australia; Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Australia. 5. School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia; Departments of Infectious Diseases and Paediatrics, Gold Coast Health, Gold Coast, Australia. 6. UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia. 7. UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia; Pathology Queensland Central Laboratory, Brisbane, Australia. 8. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; Australian Centre for Ecogenomics, The University of Queensland, Brisbane, Australia. 9. QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia. Electronic address: t.m.kidd@uq.edu.au. 10. QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia. Electronic address: scott.bell@health.qld.gov.au.
Abstract
BACKGROUND: Antimicrobial resistance in cystic fibrosis (CF) Pseudomonas aeruginosa airway infection is complex and often attributed to chromosomal mutations. How these mutations emerge in specific strains or whether particular gene mutations are clinically informative is unclear. This study focused on oprD, which encodes an outer membrane porin associated with carbapenem resistance when it is downregulated or inactivated. AIM: Determine how mutations in oprD emerge in two prevalent Australian shared CF strains of P. aeruginosa and their clinical relevance. METHODS: The two most common shared CF strains in Queensland were investigated using whole genome sequencing and their oprD sequences and antimicrobial resistance phenotypes were established. P. aeruginosa mutants with the most common oprD variants were constructed and characterised. Clinical variables were compared between people with or without evidence of infection with strains harbouring these variants. RESULTS: Frequently found nonsense mutations arising from a 1-base pair substitution in oprD evolved independently in three sub-lineages, and are likely major contributors to the reduced carbapenem susceptibility observed in the clinical isolates. Lower baseline FEV1 %predicted was identified as a risk factor for infection with a sub-lineage (odds ratio=0.97; 95% confidence interval 0.96-0.99; p<0.001). However, acquiring these sub-lineage strains did not confer an accelerated decline in FEV1 nor increase the risk of death/lung transplantation. CONCLUSIONS: Sub-lineages harbouring specific mutations in oprD have emerged and persisted in the shared strain populations. Infection with the sub-lineages was more likely in people with lower lung function, but this was not predictive of a worse clinical trajectory.
BACKGROUND: Antimicrobial resistance in cystic fibrosis (CF) Pseudomonas aeruginosa airway infection is complex and often attributed to chromosomal mutations. How these mutations emerge in specific strains or whether particular gene mutations are clinically informative is unclear. This study focused on oprD, which encodes an outer membrane porin associated with carbapenem resistance when it is downregulated or inactivated. AIM: Determine how mutations in oprD emerge in two prevalent Australian shared CF strains of P. aeruginosa and their clinical relevance. METHODS: The two most common shared CF strains in Queensland were investigated using whole genome sequencing and their oprD sequences and antimicrobial resistance phenotypes were established. P. aeruginosa mutants with the most common oprD variants were constructed and characterised. Clinical variables were compared between people with or without evidence of infection with strains harbouring these variants. RESULTS: Frequently found nonsense mutations arising from a 1-base pair substitution in oprD evolved independently in three sub-lineages, and are likely major contributors to the reduced carbapenem susceptibility observed in the clinical isolates. Lower baseline FEV1 %predicted was identified as a risk factor for infection with a sub-lineage (odds ratio=0.97; 95% confidence interval 0.96-0.99; p<0.001). However, acquiring these sub-lineage strains did not confer an accelerated decline in FEV1 nor increase the risk of death/lung transplantation. CONCLUSIONS: Sub-lineages harbouring specific mutations in oprD have emerged and persisted in the shared strain populations. Infection with the sub-lineages was more likely in people with lower lung function, but this was not predictive of a worse clinical trajectory.
Authors: Derek S Sarovich; Erin P Price; Danielle E Madden; Olusola Olagoke; Timothy Baird; Jane Neill; Kay A Ramsay; Tamieka A Fraser; Scott C Bell Journal: Antimicrob Agents Chemother Date: 2022-04-25 Impact factor: 5.938