scholarly journals Pseudomonas aeruginosa enhances the efficacy of norfloxacin against Staphylococcus aureus biofilms

2020 ◽  
Author(s):  
Giulia Orazi ◽  
Fabrice Jean-Pierre ◽  
George A. O’Toole
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Respiratory Infections ◽  
Multiple Infection ◽  
Bacterial Biofilms ◽  
Interspecies Interactions ◽  
Chronic Infections ◽  
Susceptibility Profiles

AbstractThe thick mucus within the airways of individuals with cystic fibrosis (CF) promotes frequent respiratory infections that are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent pathogens that cause CF pulmonary infections, and both have been associated with worse lung function. Furthermore, the ability of P. aeruginosa and S. aureus to form biofilms promotes the establishment of chronic infections that are often difficult to eradicate using antimicrobial agents. In this study, we found that multiple LasR-regulated exoproducts of P. aeruginosa, including HQNO, siderophores, phenazines, and rhamnolipids, likely contribute to the ability of P. aeruginosa to shift S. aureus norfloxacin susceptibility profiles. Here, we observe that exposure to P. aeruginosa exoproducts leads to an increase in intracellular norfloxacin accumulation by S. aureus. We previously showed that P. aeruginosa supernatant dissipates S. aureus membrane potential, and furthermore, depletion of the S. aureus proton-motive force recapitulates the effect of P. aeruginosa supernatant on shifting norfloxacin sensitivity profiles of biofilm-grown S. aureus. From these results, we hypothesize that exposure to P. aeruginosa exoproducts leads to increased uptake of the drug and/or an impaired ability of S. aureus to efflux norfloxacin. Our results illustrate that microbially-derived products can greatly alter the ability of antimicrobial agents to kill bacterial biofilms.ImportancePseudomonas aeruginosa and Staphylococcus aureus are frequently co-isolated from multiple infection sites, including the lungs of individuals with cystic fibrosis (CF) and non-healing diabetic foot ulcers. Co-infection with P. aeruginosa and S. aureus has been shown to produce worse outcomes compared to infection with one organism alone. Furthermore, the ability of these pathogens to form biofilms enables them to cause persistent infection and withstand antimicrobial therapy. In this study, we found that P. aeruginosa-secreted products dramatically increase the ability of the antibiotic norfloxacin to kill S. aureus biofilms. Understanding how interspecies interactions alter the antibiotic susceptibility of bacterial biofilms may inform treatment decisions and inspire the development of new therapeutic strategies.

scholarly journals Pseudomonas aeruginosa PA14 Enhances the Efficacy of Norfloxacin against Staphylococcus aureus Newman Biofilms

2020 ◽  
Vol 202 (18) ◽  
Author(s):  
Giulia Orazi ◽  
Fabrice Jean-Pierre ◽  
George A. O’Toole
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Respiratory Infections ◽  
Multiple Infection ◽  
Bacterial Biofilms ◽  
Interspecies Interactions ◽  
Chronic Infections ◽  
Content Type

ABSTRACT The thick mucus within the airways of individuals with cystic fibrosis (CF) promotes frequent respiratory infections that are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent pathogens that cause CF pulmonary infections, and both are among the most common etiologic agents of chronic wound infections. Furthermore, the ability of P. aeruginosa and S. aureus to form biofilms promotes the establishment of chronic infections that are often difficult to eradicate using antimicrobial agents. In this study, we found that multiple LasR-regulated exoproducts of P. aeruginosa, including 2-heptyl-4-hydroxyquinoline N-oxide (HQNO), siderophores, phenazines, and rhamnolipids, likely contribute to the ability of P. aeruginosa PA14 to shift S. aureus Newman norfloxacin susceptibility profiles. Here, we observe that exposure to P. aeruginosa exoproducts leads to an increase in intracellular norfloxacin accumulation by S. aureus. We previously showed that P. aeruginosa supernatant dissipates the S. aureus membrane potential, and furthermore, depletion of the S. aureus proton motive force recapitulates the effect of the P. aeruginosa PA14 supernatant on shifting norfloxacin sensitivity profiles of biofilm-grown S. aureus Newman. From these results, we hypothesize that exposure to P. aeruginosa PA14 exoproducts leads to increased uptake of the drug and/or an impaired ability of S. aureus Newman to efflux norfloxacin. Surprisingly, the effect observed here of P. aeruginosa PA14 exoproducts on S. aureus Newman susceptibility to norfloxacin seemed to be specific to these strains and this antibiotic. Our results illustrate that microbially derived products can alter the ability of antimicrobial agents to kill bacterial biofilms. IMPORTANCE Pseudomonas aeruginosa and Staphylococcus aureus are frequently coisolated from multiple infection sites, including the lungs of individuals with cystic fibrosis (CF) and nonhealing diabetic foot ulcers. Coinfection with P. aeruginosa and S. aureus has been shown to produce worse outcomes compared to infection with either organism alone. Furthermore, the ability of these pathogens to form biofilms enables them to cause persistent infection and withstand antimicrobial therapy. In this study, we found that P. aeruginosa-secreted products dramatically increase the ability of the antibiotic norfloxacin to kill S. aureus biofilms. Understanding how interspecies interactions alter the antibiotic susceptibility of bacterial biofilms may inform treatment decisions and inspire the development of new therapeutic strategies.

scholarly journals Poly (acetyl arginyl) glucosamine attenuates Pseudomonas aeruginosa in a rat lung infection model

2021 ◽  
Author(s):  
Bryan Garcia ◽  
Melissa S. McDaniel ◽  
Allister J. Loughran ◽  
J. Dixon Johns ◽  
Vidya Narayanaswamy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Respiratory Infections ◽  
Bacterial Species ◽  
Membrane Integrity ◽  
Opportunistic Pathogen ◽  
Infection Model ◽  
Total Biomass ◽  
Chronic Infections

Pseudomonas aeruginosa is a common opportunistic pathogen that can cause chronic infections in multiple disease states, including respiratory infections in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Like many opportunists, P. aeruginosa forms multicellular biofilm communities that are widely thought to be an important determinant of bacterial persistence and resistance to antimicrobials and host immune effectors during chronic/recurrent infections. Poly (acetyl, arginyl) glucosamine (PAAG) is a glycopolymer which has antimicrobial activity against a broad range of bacterial species, and also has mucolytic activity which can normalize rheologic properties of cystic fibrosis mucus. In this study, we sought to evaluate the effect of PAAG on P. aeruginosa bacteria within biofilms in vitro, and in the context of experimental pulmonary infection in a rodent infection model. PAAG treatment caused significant bactericidal activity against P. aeruginosa biofilms, and a reduction in the total biomass of preformed P. aeruginosa biofilms on abiotic surfaces, as well as on the surface of immortalized cystic fibrosis human bronchial epithelial cells. Studies of membrane integrity indicated that PAAG causes changes to P. aeruginosa cell morphology and dysregulates membrane polarity. PAAG treatment reduced infection and consequent tissue inflammation in experimental P. aeruginosa rat infections. Based on these findings we conclude that PAAG represents a novel means to combat P. aeruginosa infection, which may warrant further evaluation as a therapeutic.

scholarly journals Sodium Nitrite-Mediated Killing of the Major Cystic Fibrosis Pathogens Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia under Anaerobic Planktonic and Biofilm Conditions

2010 ◽  
Vol 54 (11) ◽  
pp. 4671-4677 ◽  
Author(s):  
Tiffany A. Major ◽  
Warunya Panmanee ◽  
Joel E. Mortensen ◽  
Larry D. Gray ◽  
Niel Hoglen ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Sodium Nitrite ◽  
Burkholderia Cepacia ◽  
Airway Disease ◽  
Resistant Organism ◽  
Anaerobic Conditions ◽  
Chronic Infections ◽  
Antibiotic Resistant

ABSTRACT A hallmark of airways in patients with cystic fibrosis (CF) is highly refractory, chronic infections by several opportunistic bacterial pathogens. A recent study demonstrated that acidified sodium nitrite (A-NO2 −) killed the highly refractory mucoid form of Pseudomonas aeruginosa, a pathogen that significantly compromises lung function in CF patients (S. S. Yoon et al., J. Clin. Invest. 116:436-446, 2006). Therefore, the microbicidal activity of A-NO2 − (pH 6.5) against the following three major CF pathogens was assessed: P. aeruginosa (a mucoid, mucA22 mutant and a sequenced nonmucoid strain, PAO1), Staphylococcus aureus USA300 (methicillin resistant), and Burkholderia cepacia, a notoriously antibiotic-resistant organism. Under planktonic, anaerobic conditions, growth of all strains except for P. aeruginosa PAO1 was inhibited by 7.24 mM (512 μg ml−1 NO2 −). B. cepacia was particularly sensitive to low concentrations of A-NO2 − (1.81 mM) under planktonic conditions. In antibiotic-resistant communities known as biofilms, which are reminiscent of end-stage CF airway disease, A-NO2 − killed mucoid P. aeruginosa, S. aureus, and B. cepacia; 1 to 2 logs of cells were killed after a 2-day incubation with a single dose of ∼15 mM A-NO2 −. Animal toxicology and phase I human trials indicate that these bactericidal levels of A-NO2 − can be easily attained by aerosolization. Thus, in summary, we demonstrate that A-NO2 − is very effective at killing these important CF pathogens and could be effective in other infectious settings, particularly under anaerobic conditions where bacterial defenses against the reduction product of A-NO2 −, nitric oxide (NO), are dramatically reduced.

scholarly journals Mechanisms of Pyocyanin Toxicity and Genetic Determinants of Resistance in Staphylococcus aureus

2017 ◽  
Vol 199 (17) ◽  
Author(s):  
Michael J. Noto ◽  
William J. Burns ◽  
William N. Beavers ◽  
Eric P. Skaar
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Respiratory Infections ◽  
Severe Disease ◽  
Ros Generation ◽  
Content Type ◽  
Small Colony Variant ◽  
High Concentrations

ABSTRACT Pseudomonas aeruginosa and Staphylococcus aureus are commonly isolated from polymicrobial infections, such as wound infections and chronic respiratory infections of persons with cystic fibrosis. Despite their coisolation, P. aeruginosa produces substances toxic to S. aureus, including pyocyanin, a blue-pigmented molecule that functions in P. aeruginosa virulence. Pyocyanin inhibits S. aureus respiration, forcing it to derive energy from fermentation and adopt a small-colony variant (SCV) phenotype. The mechanisms by which S. aureus sustains infection in the presence of pyocyanin are not clear. We sought to clarify the mechanisms of pyocyanin toxicity in S. aureus as well as identify the staphylococcal factors involved in its resistance to pyocyanin toxicity. Nonrespiring S. aureus SCVs are inhibited by pyocyanin through pyocyanin-dependent reactive oxygen species (ROS) production, indicating that pyocyanin toxicity is mediated through respiratory inhibition and ROS generation. Selection on pyocyanin yielded a menadione auxotrophic SCV capable of growth on high concentrations of pyocyanin. Genome sequencing of this isolate identified mutations in four genes, including saeS, menD, NWMN_0006, and qsrR. QsrR is a quinone-sensing repressor of quinone detoxification genes. Inactivation of qsrR resulted in significant pyocyanin resistance, and additional pyocyanin resistance was achieved through combined inactivation of qsrR and menadione biosynthesis. Pyocyanin-resistant S. aureus has an enhanced capability to inactivate pyocyanin, suggesting QsrR-regulated gene products may degrade pyocyanin to alleviate toxicity. These findings demonstrate pyocyanin-mediated ROS generation as an additional mechanism of pyocyanin toxicity and define QsrR as a key mediator of pyocyanin resistance in S. aureus. IMPORTANCE Many bacterial infections occur in the presence of other microbes, where interactions between different microbes and the host impact disease. In patients with cystic fibrosis, chronic lung infection with multiple microbes results in the most severe disease manifestations. Staphylococcus aureus and Pseudomonas aeruginosa are prevalent cystic fibrosis pathogens, and infection with both is associated with worse outcomes. These organisms have evolved mechanisms of competing with one another. For example, P. aeruginosa produces pyocyanin, which inhibits S. aureus growth. Our research has identified how pyocyanin inhibits S. aureus growth and how S. aureus can adapt to survive in the presence of pyocyanin. Understanding how S. aureus sustains infection in the presence of P. aeruginosa may identify means of disrupting these microbial communities.

scholarly journals Pseudomonas aeruginosaAlginate Overproduction Promotes Coexistence withStaphylococcus aureusin a Model of Cystic Fibrosis Respiratory Infection

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Dominique H. Limoli ◽  
Gregory B. Whitfield ◽  
Tomoe Kitao ◽  
Melissa L. Ivey ◽  
Michael R. Davis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Health Outcomes ◽  
Community Dynamics ◽  
Antimicrobial Agents ◽  
Respiratory Infections ◽  
Chronic Infections ◽  
Microbial Community Dynamics ◽  
Secreted Factors ◽  
Patient Health

ABSTRACTWhile complex intra- and interspecies microbial community dynamics are apparent during chronic infections and likely alter patient health outcomes, our understanding of these interactions is currently limited. For example,Pseudomonas aeruginosaandStaphylococcus aureusare often found to coinfect the lungs of patients with cystic fibrosis (CF), yet these organisms compete under laboratory conditions. Recent observations that coinfection correlates with decreased health outcomes necessitate we develop a greater understanding of these interbacterial interactions. In this study, we tested the hypothesis thatP. aeruginosaand/orS. aureusadopts phenotypes that allow coexistence during infection. We compared competitive interactions ofP. aeruginosaandS. aureusisolates from mono- or coinfected CF patients employingin vitrococulture models.P. aeruginosaisolates from monoinfected patients were more competitive towardS. aureusthanP. aeruginosaisolates from coinfected patients. We also observed that the least competitiveP. aeruginosaisolates possessed a mucoid phenotype. Mucoidy occurs upon constitutive activation of the sigma factor AlgT/U, which regulates synthesis of the polysaccharide alginate and dozens of other secreted factors, including some previously described to killS. aureus. Here, we show that production of alginate in mucoid strains is sufficient to inhibit anti-S. aureusactivity independent of activation of the AlgT regulon. Alginate reduces production of siderophores, 2-heptyl-4-hydroxyquinolone-N-oxide (HQNO), and rhamnolipids—each required for efficient killing ofS. aureus. These studies demonstrate alginate overproduction may be an important factor drivingP. aeruginosacoinfection withS. aureus.IMPORTANCENumerous deep-sequencing studies have revealed the microbial communities present during respiratory infections in cystic fibrosis (CF) patients are diverse, complex, and dynamic. We now face the challenge of determining the influence of these community dynamics on patient health outcomes and identifying candidate targets to modulate these interactions. We make progress toward this goal by determining that the polysaccharide alginate produced by mucoid strains ofP. aeruginosais sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompeteS. aureus, when the microbes are grown in coculture; thus we propose a mechanism whereby mucoidP. aeruginosacan coexist withS. aureus. Finally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens.

scholarly journals Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Giulia Orazi ◽  
George A. O’Toole
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Protein Synthesis ◽  
Respiratory Pathogens ◽  
Interspecies Interactions ◽  
Protein Synthesis Inhibitors ◽  
Lung Infections ◽  
Polymicrobial Infections

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. 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.

scholarly journals Surfaceome and Exoproteome Dynamics in Dual-Species Pseudomonas aeruginosa and Staphylococcus aureus Biofilms

2021 ◽  
Vol 12 ◽  
Author(s):  
Inés Reigada ◽  
Paola San-Martin-Galindo ◽  
Shella Gilbert-Girard ◽  
Jacopo Chiaro ◽  
Vincenzo Cerullo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Quantitative Proteomics ◽  
Single Species ◽  
Pigment Production ◽  
Bacterial Biofilms ◽  
Label Free ◽  
Host Defenses ◽  
Chronic Infections ◽  
And Staphylococcus Aureus

Bacterial biofilms are an important underlying cause for chronic infections. By switching into the biofilm state, bacteria can evade host defenses and withstand antibiotic chemotherapy. Despite the fact that biofilms at clinical and environmental settings are mostly composed of multiple microbial species, biofilm research has largely been focused on single-species biofilms. In this study, we investigated the interaction between two clinically relevant bacterial pathogens (Staphylococcus aureus and Pseudomonas aeruginosa) by label-free quantitative proteomics focusing on proteins associated with the bacterial cell surfaces (surfaceome) and proteins exported/released to the extracellular space (exoproteome). The changes observed in the surfaceome and exoproteome of P. aeruginosa pointed toward higher motility and lower pigment production when co-cultured with S. aureus. In S. aureus, lower abundances of proteins related to cell wall biosynthesis and cell division, suggesting increased persistence, were observed in the dual-species biofilm. Complementary phenotypic analyses confirmed the higher motility and the lower pigment production in P. aeruginosa when co-cultured with S. aureus. Higher antimicrobial tolerance associated with the co-culture setting was additionally observed in both species. To the best of our knowledge, this study is among the first systematic explorations providing insights into the dynamics of both the surfaceome and exoproteome of S. aureus and P. aeruginosa dual-species biofilms.

scholarly journals Inactivation of the Mismatch Repair System in Pseudomonas aeruginosa Attenuates Virulence but Favors Persistence of Oropharyngeal Colonization in Cystic Fibrosis Mice

2007 ◽  
Vol 189 (9) ◽  
pp. 3665-3668 ◽  
Author(s):  
Ana Mena ◽  
María D. Maciá ◽  
Nuria Borrell ◽  
Bartolomé Moya ◽  
Teresa de Francisco ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Mismatch Repair ◽  
Respiratory Infections ◽  
Repair System ◽  
Chronic Infections ◽  
Mismatch Repair System ◽  
Colonization Potential

ABSTRACT The inactivation of the mismatch repair (MMR) system of Pseudomonas aeruginosa modestly reduced in vitro fitness, attenuated virulence in murine models of acute systemic and respiratory infections, and decreased the initial oropharyngeal colonization potential. In contrast, the inactivation of the MMR system favored long-term persistence of oropharyngeal colonization in cystic fibrosis mice. These results may help in understanding the reasons for the low and high prevalences, respectively, of hypermutable P. aeruginosa strains in acute and chronic infections.

scholarly journals Pseudomonas aeruginosaincreases the sensitivity of biofilm-grownStaphylococcus aureusto membrane-targeting antiseptics and antibiotics

2019 ◽  
Author(s):  
Giulia Orazi ◽  
Kathryn L. Ruoff ◽  
George A. O’Toole
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Chronic Wounds ◽  
Respiratory Infections ◽  
Membrane Targeting ◽  
Bacterial Membranes ◽  
Log Reduction ◽  
Tract Infections

AbstractPseudomonas aeruginosaandStaphylococcus aureusoften cause chronic, recalcitrant infections in large part due to their ability to form biofilms. The biofilm mode of growth enables these organisms to withstand antibacterial insults that would effectively eliminate their planktonic counterparts. We found thatP. aeruginosasupernatant increased the sensitivity ofS. aureusbiofilms to multiple antimicrobial compounds, including fluoroquinolones and membrane-targeting antibacterial agents, including the antiseptic chloroxylenol. Treatment ofS. aureuswith the antiseptic chloroxylenol alone did not decrease biofilm cell viability; however, the combination of chloroxylenol andP. aeruginosasupernatant led to a 4-log reduction inS. aureusbiofilm viability compared to exposure to chloroxylenol alone. We found that theP. aeruginosa-produced small molecule 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO) is responsible for the observed heightened sensitivity ofS. aureusto chloroxylenol. Similarly, HQNO increased the susceptibility ofS. aureusbiofilms to other compounds, including both traditional and non-traditional antibiotics, which permeabilize bacterial membranes. Genetic and phenotypic studies support a model whereby HQNO causes an increase inS. aureusmembrane fluidity, thereby improving the efficacy of membrane-targeting antiseptics and antibiotics. Importantly, our data show thatP. aeruginosaexoproducts can enhance the ability of various antimicrobial agents to kill biofilm populations ofS. aureusthat are typically difficult to eradicate, providing a path for the discovery of new biofilm-targeting antimicrobial strategies.ImportanceThe thick mucus in the airways of cystic fibrosis (CF) patients predisposes them to frequent, polymicrobial respiratory infections.Pseudomonas aeruginosaandStaphylococcus aureusare frequently co-isolated from the airways of individuals with CF, as well as from diabetic foot ulcers and other wounds. Both organisms form biofilms, which are notoriously difficult to eradicate and promote chronic infection. In this study, we have shownP. aeruginosasecreted factors can increase the efficacy of compounds that alone have little or no bactericidal activity againstS. aureusbiofilms. In particular, we discovered thatP. aeruginosaexoproducts can potentiate the anti-staphylococcal activity of phenol-based antiseptics and other membrane-active drugs, including non-traditional antibiotics. Our findings illustrate that polymicrobial interactions can dramatically increase antibacterial efficacyin vitro, and may guide new approaches to target persistent infections, such as those commonly found in respiratory tract infections and in chronic wounds.

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