Selective Sweeps and Parallel Pathoadaptation Drive Pseudomonas aeruginosa Evolution in the Cystic Fibrosis Lung

Abstract

Pulmonary infections caused by Pseudomonas aeruginosa are a recalcitrant problem in cystic fibrosis (CF) patients. While the clinical implications and long-term evolutionary patterns of these infections are well studied, we know little about the short-term population dynamics that enable this pathogen to persist despite aggressive antimicrobial therapy. Here, we describe a short-term population genomic analysis of 233 P. aeruginosa isolates collected from 12 sputum specimens obtained over a 1-year period from a single patient. Whole-genome sequencing and antimicrobial susceptibility profiling identified the expansion of two clonal lineages. The first lineage originated from the coalescence of the entire sample less than 3 years before the end of the study and gave rise to a high-diversity ancestral population. The second expansion occurred 2 years later and gave rise to a derived population with a strong signal of positive selection. These events show characteristics consistent with recurrent selective sweeps. While we cannot identify the specific mutations responsible for the origins of the clonal lineages, we find that the majority of mutations occur in loci previously associated with virulence and resistance. Additionally, approximately one-third of all mutations occur in loci that are mutated multiple times, highlighting the importance of parallel pathoadaptation. One such locus is the gene encoding penicillin-binding protein 3, which received three independent mutations. Our functional analysis of these alleles shows that they provide differential fitness benefits dependent on the antibiotic under selection. These data reveal that bacterial populations can undergo extensive and dramatic changes that are not revealed by lower-resolution analyses.

Deciphering the Resistome of the Widespread Pseudomonas aeruginosa Sequence Type 175 International High-Risk Clone through Whole-Genome Sequencing

“…On the other hand, ftsI (PBP3) mutations emerged independently in three different ST175 isolates (Tables 1 and 2). These findings suggest that PBP3 is under strong mutational pressure, in agreement with recent data showing that PBP3 mutations emerge frequently during the course of chronic infection in CF (41). Likewise, recent studies show that PBP3 mutations emerge frequently upon meropenem exposure in vitro (42).…”

Evolution of Pseudomonas aeruginosa Antimicrobial Resistance and Fitness under Low and High Mutation Rates

“…Therefore, these results indicate that PBP3 is a major unexpected target for meropenem resistance development that should be explored among clinical strains. Indeed, the positive selection of PBP3 mutations was documented in a very recent study monitoring the evolution of P. aeruginosa in the lungs of chronically infected cystic fibrosis patients (40), although potential links with meropenem exposure remain to be explored.…”

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

“…Compensatory mutations in the clinical CF isolates are thought to provide differential fitness benefits, which are advantageous within the CF lung environment (46). Fitness tradeoffs, where beneficial adaptations that improve fitness under one environmental condition that may lead to compensatory loss of other traits, have been described (47).…”