Affiliation:
1. University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, Maryland, USA
2. University of Maryland School of Medicine, Department of Microbiology and Immunology, Baltimore, Maryland, USA
Abstract
ABSTRACT
Cystic fibrosis (CF) is a heritable disease characterized by chronic, polymicrobial lung infections. While
Staphylococcus aureus
is the dominant lung pathogen in young CF patients,
Pseudomonas aeruginosa
becomes predominant by adulthood.
P. aeruginosa
produces a variety of antimicrobials that likely contribute to this shift in microbial populations. In particular, secretion of 2-alkyl-4(1
H
)-quinolones (AQs) contributes to lysis of
S. aureus
in coculture, providing an iron source to
P. aeruginosa
both
in vitro
and
in vivo
. We previously showed that production of one such AQ, the
Pseudomonas
quinolone signal (PQS), is enhanced by iron depletion and that this induction is dependent upon the iron-responsive PrrF small RNAs (sRNAs). Here, we demonstrate that antimicrobial activity against
S. aureus
during coculture is also enhanced by iron depletion, and we provide evidence that multiple AQs contribute to this activity. Strikingly, a
P. aeruginosa
Δ
prrF
mutant, which produces very little PQS in monoculture, was capable of mediating iron-regulated growth suppression of
S. aureus
. We show that the presence of
S. aureus
suppresses the Δ
prrF1
,
2
mutant's defect in iron-regulated PQS production, indicating that a PrrF-independent iron regulatory pathway mediates AQ production in coculture. We further demonstrate that iron-regulated antimicrobial production is conserved in multiple
P. aeruginosa
strains, including clinical isolates from CF patients. These results demonstrate that iron plays a central role in modulating interactions of
P. aeruginosa
with
S. aureus
. Moreover, our studies suggest that established iron regulatory pathways of these pathogens are significantly altered during polymicrobial infections.
IMPORTANCE
Chronic polymicrobial infections involving
Pseudomonas aeruginosa
and
Staphylococcus aureus
are a significant cause of morbidity and mortality, as the interplay between these two organisms exacerbates infection. This is in part due to enhanced production of antimicrobial metabolites by
P. aeruginosa
when these two species are cocultured. Using both established and newly developed coculture techniques, this report demonstrates that iron depletion increases
P. aeruginosa
's ability to suppress growth of
S. aureus
. These findings present a novel role for iron in modulating microbial interaction and provide the basis for understanding how essential nutrients drive polymicrobial infections.
Publisher
American Society for Microbiology
Subject
Molecular Biology,Microbiology
Cited by
71 articles.
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