Interspecific Small Molecule Interactions between Clinical Isolates of Pseudomonas aeruginosa and Staphylococcus aureus from Adult Cystic Fibrosis Patients

Fugère, Alexandre; Séguin, David Lalonde; Mitchell, Gabriel; Déziel, Éric; Dekimpe, Valérie; Cantin, André M.; Frost, Éric; Malouin, François

doi:10.1371/journal.pone.0086705

Cited by 80 publications

(93 citation statements)

References 59 publications

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“…Thus, a large number of quorum sensors act as cell signaling molecules that regulate gene expression within as well as between microbial populations and in the host (345)(346)(347). The extent of biofilm formation and synthesis of pathogenicity factors correlated with species-specific levels of quorum sensors (348)(349)(350). P. aeruginosa quorum sensors were isolated from sputa of CF patients (351,352).…”

Section: Signaling and Virulencementioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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Section: Signaling and Virulencementioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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“…This striking negative clinical correlation between S. aureus and P. aeruginosa during teenage years and young adulthood has driven several in vitro and in vivo studies geared toward characterizing the interbacterial interactions of these two organisms (36)(37)(38)(39)(40)(41)(42)(43)(44). These previous studies have found that P. aeruginosa secretes various antistaphylococcal products and proteases, such as LasA, that can cause both biofilm dispersion and cell lysis of S. aureus (42,45).…”

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confidence: 99%

“…These previous studies have found that P. aeruginosa secretes various antistaphylococcal products and proteases, such as LasA, that can cause both biofilm dispersion and cell lysis of S. aureus (42,45). Further, P. aeruginosa produces several inhibitors of S. aureus respiration, including hydrogen cyanide, quinoline N-oxides, and the phenazine pyocyanin (41,(46)(47)(48). P. aeruginosa has also been described to benefit from coculture with S. aureus by using this Gram-positive organism as an iron source (43) and a cue to produce extracellular virulence factors against both prokaryotic neighbors and the host (49).…”

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confidence: 99%

“…P. aeruginosa has also been described to benefit from coculture with S. aureus by using this Gram-positive organism as an iron source (43) and a cue to produce extracellular virulence factors against both prokaryotic neighbors and the host (49). In response to the hostile environment, S. aureus may adapt to P. aeruginosa exoproducts, particularly in the presence of 2-heptyl-4-hydroxyquinoline Noxide (HQNO), through increased biofilm formation (41) or increased frequency of SCVs (50,51).…”

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Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model

et al. 2015

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The airways of patients with cystic fibrosis are colonized with diverse bacterial communities that change dynamically during pediatric years and early adulthood. Staphylococcus aureus is the most prevalent pathogen during early childhood, but during late teens and early adulthood, a shift in microbial composition occurs leading to Pseudomonas aeruginosa community predominance in ϳ50% of adults. We developed a robust dual-bacterial in vitro coculture system of P. aeruginosa and S. aureus on monolayers of human bronchial epithelial cells homozygous for the ⌬F508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation to better model the mechanisms of this interaction. We show that P. aeruginosa drives the S. aureus expression profile from that of aerobic respiration to fermentation. This shift is dependent on the production of both 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) and siderophores by P. aeruginosa. Furthermore, S. aureus-produced lactate is a carbon source that P. aeruginosa preferentially consumes over medium-supplied glucose. We find that initially S. aureus and P. aeruginosa coexist; however, over extended coculture P. aeruginosa reduces S. aureus viability, also in an HQNO-and P. aeruginosa siderophore-dependent manner. Interestingly, S. aureus small-colony-variant (SCV) genetic mutant strains, which have defects in their electron transport chain, experience reduced killing by P. aeruginosa compared to their wild-type parent strains; thus, SCVs may provide a mechanism for persistence of S. aureus in the presence of P. aeruginosa. We propose that the mechanism of P. aeruginosa-mediated killing of S. aureus is multifactorial, requiring HQNO and P. aeruginosa siderophores as well as additional genetic, environmental, and nutritional factors. IMPORTANCEIn individuals with cystic fibrosis, Staphylococcus aureus is the primary respiratory pathogen during childhood. During adulthood, Pseudomonas aeruginosa predominates and correlates with worse patient outcome. The mechanism(s) by which P. aeruginosa outcompetes or kills S. aureus is not well understood. We describe an in vitro dual-bacterial species coculture system on cystic fibrosis-derived airway cells, which models interactions relevant to patients with cystic fibrosis. Further, we show that molecules produced by P. aeruginosa additively induce a transition of S. aureus metabolism from aerobic respiration to fermentation and eventually lead to loss of S. aureus viability. Elucidating the molecular mechanisms of P. aeruginosa community predominance can provide new therapeutic targets and approaches to impede this microbial community transition and subsequent patient worsening. C omplex polymicrobial communities colonize the airways of cystic fibrosis (CF) patients within the first month of life (1). Culture-independent studies have revealed the simultaneous presence of numerous bacterial taxa, fungi, and viruses in respiratory samples from CF patients at all stages of life (2-8). This abundance of microbes colonizing the respiratory ...

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“…For example, peptidoglycan shed by S. aureus was recently found to stimulate production of virulence factors in P. aeruginosa and thereby increase its lytic activity and virulence in a Drosophila model of infection (1). In addition, P. aeruginosa exoproducts were found to inhibit S. aureus respiration, induce resistance toward antibiotic killing (9), and stimulate pigment (e.g., staphyloxanthin) production, virulence, and biofilm formation by S. aureus (10)(11)(12). The virulence mechanisms of P. aeruginosa and S. aureus and their regulation have been widely studied (13)(14)(15).…”

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Staphylococcus aureus Alters Growth Activity, Autolysis, and Antibiotic Tolerance in a Human Host-Adapted Pseudomonas aeruginosa Lineage

et al. 2014

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Interactions among members of polymicrobial infections or between pathogens and the commensal flora may determine disease outcomes. Pseudomonas aeruginosa and Staphylococcus aureus are important opportunistic human pathogens and are both part of the polymicrobial infection communities in human hosts. In this study, we analyzed the in vitro interaction between S. aureus and a collection of P. aeruginosa isolates representing different evolutionary steps of a dominant lineage, DK2, that have evolved through decades of growth in chronically infected patients. While the early adapted P. aeruginosa DK2 strains outcompeted S. aureus during coculture on agar plates, we found that later P. aeruginosa DK2 strains showed a commensal-like interaction, where S. aureus was not inhibited by P. aeruginosa and the growth activity of P. aeruginosa was enhanced in the presence of S. aureus. This effect is mediated by one or more extracellular S. aureus proteins greater than 10 kDa, which also suppressed P. aeruginosa autolysis and prevented killing by clinically relevant antibiotics through promoting small-colony variant (SCV) formation. The commensal interaction was abolished with S. aureus strains mutated in the agr quorum sensing system or in the SarA transcriptional virulence regulator, as well as with strains lacking the proteolytic subunit, ClpP, of the Clp protease. Our results show that during evolution of a dominant cystic fibrosis lineage of P. aeruginosa, a commensal interaction potential with S. aureus has developed. M ost microbial species are embedded within mixed-species communities where mutualistic, antagonistic, and neutral interactions within the community control behaviors and activities of the individual species. In relation to microbial infections, it is becoming clear that interactions between bacterial pathogens and other microbial species present at the infection site (either coinfecting pathogens or commensal bacteria) can result in altered pathogen behaviors such as enhanced virulence (1, 2), biofilm formation (3), and antibiotic tolerance (4), which may influence disease progression and clinical outcome of the infection. Despite advances in elucidating the molecular details underlying microbial interactive processes, the extent to which evolutionary processes remodel interspecies interactions during the course of infection and therapy is currently not understood. Thus, studies of interaction patterns between species and the evolution within polymicrobial infections are a critical first step toward developing novel interference strategies against such infections.Chronic cystic fibrosis (CF) airway infections caused by the bacterium Pseudomonas aeruginosa offer optimal opportunities to study evolutionary dynamics within a natural environment because of systematic routine sampling of the ecosystem over extended time periods (years) and because of the well-characterized ecological properties of the system (5). We have recently determined the genetic basis of adaptation in a highly successful P. aeruginosa ...

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Interspecific Small Molecule Interactions between Clinical Isolates of Pseudomonas aeruginosa and Staphylococcus aureus from Adult Cystic Fibrosis Patients

Cited by 80 publications

References 59 publications

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model

Staphylococcus aureus Alters Growth Activity, Autolysis, and Antibiotic Tolerance in a Human Host-Adapted Pseudomonas aeruginosa Lineage

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