Polymicrobial Biofilms in Cystic Fibrosis Lung Infections: Effects on Antimicrobial Susceptibility

Galdino, Anna Clara Milesi; Vaillancourt, Mylène; Celedonio, Diana; Jorth, Peter

doi:10.1007/978-3-031-15349-5_7

Cited by 3 publications

(2 citation statements)

References 214 publications

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“…Longitudinal sampling of single or small subsets of isolates from a population only reflects a fraction of the total evolutionary pathways exhibited within a population and may result in significant underestimation of the diversity of antimicrobial susceptibility profiles. As population diversity may impact infection outcomes via heteroresistance ( 31 ), microbial social interactions ( 32 , 33 ), or the ability of a population to survive evolutionary bottlenecks ( 3 ), this warrants a shift in our sampling and susceptibility testing of chronic microbial infections to reflect our understanding of them as complex, dynamic populations. A few studies have thoroughly investigated population diversity in this infection context, in which their analyses were focused on (i) phenotypic diversity ( 34 – 38 ), (ii) genetic analyses via pooled population sequencing ( 39 , 40 ), or (iii) both extensive sequencing and phenotyping, but lacking analysis linking the two at the isolate level ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity of Pseudomonas aeruginosa populations in cystic fibrosis lung infection

Vanderwoude,

Azimi,

Read

et al. 2024

mBio

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Pseudomonas aeruginosa is an opportunistic pathogen which causes chronic, drug-resistant lung infections in cystic fibrosis (CF) patients. In this study, we explore the role of genomic diversification and evolutionary trade-offs in antimicrobial resistance (AMR) diversity within P. aeruginosa populations sourced from CF lung infections. We analyzed 300 clinical isolates from four CF patients (75 per patient) and found that genomic diversity is not a consistent indicator of phenotypic AMR diversity. Remarkably, some genetically less diverse populations showed AMR diversity comparable to those with significantly more genetic variation. We also observed that hypermutator strains frequently exhibited increased sensitivity to antimicrobials, contradicting expectations from their treatment histories. Investigating potential evolutionary trade-offs, we found no substantial evidence of collateral sensitivity among aminoglycoside, beta-lactam, or fluoroquinolone antibiotics, nor did we observe trade-offs between AMR and growth in conditions mimicking CF sputum. Our findings suggest that (i) genomic diversity is not a prerequisite for phenotypic AMR diversity, (ii) hypermutator populations may develop increased antimicrobial sensitivity under selection pressure, (iii) collateral sensitivity is not a prominent feature in CF strains, and (iv) resistance to a single antibiotic does not necessarily lead to significant fitness costs. These insights challenge prevailing assumptions about AMR evolution in chronic infections, emphasizing the complexity of bacterial adaptation during infection. IMPORTANCE Upon infection in the cystic fibrosis (CF) lung, Pseudomonas aeruginosa rapidly acquires genetic mutations, especially in genes involved in antimicrobial resistance (AMR), often resulting in diverse, treatment-resistant populations. However, the role of bacterial population diversity within the context of chronic infection is still poorly understood. In this study, we found that hypermutator strains of P. aeruginosa in the CF lung undergoing treatment with tobramycin evolved increased sensitivity to tobramycin relative to non-hypermutators within the same population. This finding suggests that antimicrobial treatment may only exert weak selection pressure on P. aeruginosa populations in the CF lung. We further found no evidence for collateral sensitivity in these clinical populations, suggesting that collateral sensitivity may not be a robust, naturally occurring phenomenon for this microbe.

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Section: Introductionmentioning

confidence: 99%

The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity of Pseudomonas aeruginosa populations in cystic fibrosis lung infection

Vanderwoude,

Azimi,

Read

et al. 2024

mBio

View full text Add to dashboard Cite

show abstract

“…Longitudinal sampling of single or small subsets of isolates from a population only reflects a fraction of the total evolutionary pathways exhibited within a population and may result in significant underestimation of the diversity of antimicrobial susceptibility profiles. As population diversity may impact infection outcomes via heteroresistance [31], microbial social interactions [32,33], or the ability of a population to survive evolutionary bottlenecks [3], this warrants a shift in our sampling and susceptibility testing of chronic microbial infections to reflect our understanding of them as complex, dynamic populations. A few studies have thoroughly investigated population diversity in this infection context, in which their analyses were focused on (i) phenotypic diversity [34][35][36][37][38]; (ii) genetic analyses via pooled population sequencing [39,40]; or (iii) both extensive sequencing and phenotyping, but lacking analysis linking the two at the isolate-level [6].…”

mentioning

confidence: 99%

The Role of Hypermutation and Collateral Sensitivity in Antimicrobial Resistance Diversity ofPseudomonas aeruginosaPopulations in Cystic Fibrosis Lung Infection

Vanderwoude

Azimi

Read

et al. 2023

Preprint

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Pseudomonas aeruginosa is the predominant bacterial pathogen in the cystic fibrosis (CF) lung, establishing a chronic, drug-resistant infection often via a single adapting and diversifying strain. In this study, we collected a bio-repository of 300 isolates of P. aeruginosa from four CF patients to unravel the extent of within-patient genomic diversity in CF lung infection; elucidate the evolutionary processes by which this diversity is generated; and understand how diversification impacts antimicrobial resistance. We found that populations of P. aeruginosa in the CF lung displayed patient specific genomic diversity ranging from 1 to 199 median pairwise SNPs, and 31 to 4,592 total SNPs within a population. Diversification was driven by a combination of de novo mutations, recombination, and variations in gene content, with the highest levels of population diversity associated with the presence of DNA mismatch repair mutants. Populations with higher levels of genomic diversity displayed increased variation in antibiotic resistance phenotypes; however, even populations with lower genomic diversity displayed substantial diversity in resistance profiles. Intriguingly, we found evidence that mutations in DNA mismatch repair can facilitate the evolution of seemingly undesirable traits in vivo, such as increased sensitivity to certain antimicrobials. Overall, our findings highlight that (i) P. aeruginosa genomic population diversity in chronic CF lung infection is highly variable between patients; (ii) hypermutator populations can evolve increased sensitivity to antimicrobials even under apparent antibiotic selection; and that (iii) current methods of single-isolate sampling and susceptibility testing should be re-evaluated in the study of chronic P. aeruginosa infection.

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Emerging strategies to target virulence in Pseudomonas aeruginosa respiratory infections

Hibbert,

Whiteley,

Renshaw

et al. 2023

Critical Reviews in Microbiology

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Polymicrobial Biofilms in Cystic Fibrosis Lung Infections: Effects on Antimicrobial Susceptibility

Cited by 3 publications

References 214 publications

The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity of Pseudomonas aeruginosa populations in cystic fibrosis lung infection

The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity of Pseudomonas aeruginosa populations in cystic fibrosis lung infection

The Role of Hypermutation and Collateral Sensitivity in Antimicrobial Resistance Diversity ofPseudomonas aeruginosaPopulations in Cystic Fibrosis Lung Infection

Emerging strategies to target virulence in Pseudomonas aeruginosa respiratory infections

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