Abstract
Pseudomonas aeruginosa is a leading pathogen that has become increasingly resistant to the fluoroquinolone antibiotics due to widespread prescribing. Adverse outcomes have been shown for patients infected with fluoroquinolone-resistant strains. The type III secretion system (TTSS) is a major virulence determinant during acute infections through the injection of effector toxins into host cells. Most strains exhibit a unique TTSS virulence genotype defined by the presence of either exoS or exoU gene encoding two of the effector toxins, ExoS and ExoU, respectively. Specific TTSS effector genotype has been shown previously to differentially impact virulence in pneumonia. In this study, we examined the relationship between TTSS effector genotype and fluoroquinolone resistance mechanisms in a collection of 270 respiratory isolates. We found that a higher proportion of exoU+ strains were fluoroquinolone-resistant compared to exoS+ strains (63% vs 49%, p = 0.03) despite its lower overall prevalence (38% exoU+ vs 56% exoS+). Results from sequencing the quinolone resistance determining regions (QRDRs) of the 4 target genes (gyrA, gyrB, parC, parE) indicated that strains containing the exoU gene were more likely to acquire ≥2 mutations than exoS+ strains at MICs ≤8 µg/ml (13% vs none) and twice as likely to have mutations in both gyrA and parC than exoS+ strains (48% vs 24% p = 0.0439). Our findings indicate that P. aeruginosa strains differentially develop resistance-conferring mutations that correlate with TTSS effector genotype and the more virulent exoU+ subpopulation. Differences in mutational processes by virulence genotype that were observed suggest co-evolution of resistance and virulence traits favoring a more virulent genotype in the quinolone-rich clinical environment.
Highlights
Pseudomonas aeruginosa is a gram-negative pathogen that causes opportunistic infections in susceptible hosts
We found that a higher proportion of exoU+ strains were fluoroquinolone-resistant compared to exoS+ strains (63% vs 49%, p = 0.03) despite its lower overall prevalence (38% exoU+ vs 56% exoS+)
Our findings indicate that P. aeruginosa strains differentially develop resistance-conferring mutations that correlate with type III secretion system (TTSS) effector genotype and the more virulent exoU+
Summary
Pseudomonas aeruginosa is a gram-negative pathogen that causes opportunistic infections in susceptible hosts. It is a leading cause of acute pneumonia in hospitalized patients and is responsible for chronic lung infection in patients with cystic fibrosis. Its ability to cause both acute and chronic infections can be attributed to its broad arsenal of virulence factors. The type III secretion system (TTSS) has been shown to be a major virulence determinant in the pathogenesis of acute infections. P. aeruginosa utilizes the TTSS to deliver effector toxins (ExoS, ExoU, ExoY, and ExoT) directly into host cells, which can cause rapid cell necrosis or can modulate the actin cytoskeleton, allowing the pathogen to invade host cells and evade phagocytosis [1].
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