Affiliation:
1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
Abstract
ABSTRACT
The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections.
Pseudomonas aeruginosa
and
Staphylococcus aureus
are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether
P. aeruginosa
influences the susceptibility of
S. aureus
to frontline antibiotics used to treat CF lung infections. Using our
in vitro
coculture model, we observed that addition of
P. aeruginosa
supernatants to
S. aureus
biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of
S. aureus
to vancomycin. Mutant analyses showed that 2-
n
-heptyl-4-hydroxyquinoline
N
-oxide (HQNO), a component of the
P. aeruginosa Pseudomonas
quinolone signal (PQS) system, protects
S. aureus
from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of
P. aeruginosa
to protect
S. aureus
from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO,
P. aeruginosa
supernatant, and growth under anoxia decreased
S. aureus
growth, likely explaining why this cell wall-targeting antibiotic is less effective.
P. aeruginosa
supernatant did not confer additional protection to slow-growing
S. aureus
small colony variants. Importantly,
P. aeruginosa
supernatant protects
S. aureus
from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby
P. aeruginosa
causes
S. aureus
to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in
S. aureus
growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis.
IMPORTANCE
Cystic fibrosis (CF) lung infections are chronic and difficult to eradicate.
Pseudomonas aeruginosa
and
Staphylococcus aureus
are two of the most prevalent respiratory pathogens in CF patients and are associated with poor patient outcomes. Both organisms adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these infections. Here, we show that
P. aeruginosa
exoproducts decrease the sensitivity of
S. aureus
biofilm and planktonic populations to vancomycin, a frontline antibiotic used to treat methicillin-resistant
S. aureus
in CF patients.
P. aeruginosa
also protects
S. aureus
from other cell wall-active antibiotics as well as various classes of protein synthesis inhibitors. Thus, interspecies interactions can have dramatic and unexpected consequences on antibiotic sensitivity. This study underscores the potential impact of interspecies interactions on antibiotic efficacy in the context of complex, polymicrobial infections.
Funder
Munck Pferrerkorn Fund
HHS | National Institutes of Health
HHS | NIH | National Institute of General Medical Sciences
Cystic Fibrosis Foundation
Publisher
American Society for Microbiology
Cited by
136 articles.
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