Pseudomonas aeruginosa Exoenzyme S as a Pathogenic Determinant in Respiratory Infections

2015 ◽  
pp. 27-35 ◽  
Author(s):  
Donald E. Woods ◽  
Marina To ◽  
Pamela A. Sokol
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Respiratory Infections ◽  
Exoenzyme S ◽  
Pathogenic Determinant

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 Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity

2018 ◽  
Vol 143 ◽  
pp. 568-576 ◽  
Author(s):  
Michael Saleeb ◽  
Charlotta Sundin ◽  
Öznur Aglar ◽  
Ana Filipa Pinto ◽  
Mahsa Ebrahimi ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Exoenzyme S ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Adp Ribosyltransferase

The frequency of genes encoding exotoxin A and exoenzyme S in Pseudomonas aeruginosa strains isolated from burn patients

Burns ◽  
2016 ◽  
Vol 42 (5) ◽  
pp. 1116-1120 ◽  
Author(s):  
Azar Dokht Khosravi ◽  
Fatemeh Shafie ◽  
Effat Abbasi Montazeri ◽  
Soodabeh Rostami
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Burn Patients ◽  
Exotoxin A ◽  
Exoenzyme S ◽  
Genes Encoding

The Role of Exoenzyme S in Infections with Pseudomonas aeruginosa

1985 ◽  
Vol 152 (4) ◽  
pp. 716-721 ◽  
Author(s):  
T. I. Nicas ◽  
J. Bradley ◽  
J. E. Lochner ◽  
B. H. Iglewski
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Exoenzyme S

scholarly journals Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells

2018 ◽  
Vol 314 (4) ◽  
pp. L635-L641 ◽  
Author(s):  
Manon Ruffin ◽  
Lucie Roussel ◽  
Émilie Maillé ◽  
Simon Rousseau ◽  
Emmanuelle Brochiero
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Respiratory Infections ◽  
Bronchial Epithelial Cell ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bronchial Epithelial ◽  
Primary Bronchial Epithelial Cell ◽  
Beneficial Impact

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

Nontypeable Haemophilus influenzae infection impedes Pseudomonas aeruginosa colonization and persistence in mouse respiratory tract

2021 ◽  
Author(s):  
Natalie Lindgren ◽  
Lea Novak ◽  
Benjamin C. Hunt ◽  
Melissa S. McDaniel ◽  
W. Edward Swords
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Species ◽  
Young Patients ◽  
Nontypeable Haemophilus Influenzae ◽  
Potential Significance ◽  
And Diffusion

Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature, and the predominant bacterial species undergo a predictable series of changes as patients age. Young patients have populations dominated by opportunists that are typically found within the microbiome of the human nasopharynx, such as nontypeable Haemophilus influenzae (NTHi); these are eventually supplanted and the population within the CF lung is later dominated by pathogens such as Pseudomonas aeruginosa ( Pa ). In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential respiratory infection of mice with NTHi followed by Pa resulted in significantly lower Pa as compared to infection with Pa alone. Coinfected mice also had reduced airway tissue damage and lower levels of inflammatory cytokines as compared with Pa infected mice. Similar results were observed after instillation of heat-inactivated NTHi bacteria or purified NTHi lipooligosaccharide (LOS) endotoxin prior to Pa introduction. Based on these results, we conclude that NTHi significantly reduces susceptibility to subsequent Pa infection, most likely due to priming of host innate immunity rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals Antimicrobial drug sensitivity pattern of Pseudomonas aeruginosa in respiratory infections

2017 ◽  
Vol 6 (7) ◽  
pp. 1591
Author(s):  
Syed S. Ameen ◽  
Shanmukananda Prakash ◽  
Laxminarayana Bairy K. ◽  
Shahabuddin Soherwardi
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Respiratory Infections ◽  
Tertiary Care ◽  
Empirical Therapy ◽  
Multidrug Resistant ◽  
Resistance Rate ◽  
Mortality And Morbidity ◽  
Antimicrobial Susceptibility Pattern ◽  
Sensitivity Pattern ◽  
Male Preponderance

Background: Pseudomonas aeruginosa, a gram-negative pathogen commonly associated with nosocomial infections is the most widespread multidrug-resistant pathogen causing pneumonia in hospitalized patients. Inadequate empirical therapy has been associated with high mortality and morbidity. Objective: To evaluate and analyze the antimicrobial susceptibility pattern of P. aeruginosa in respiratory infections in a tertiary care hospital.Methods: The study was carried out at Kasturba Hospital, Manipal from Jan 2011 to Dec 2011. Specimens of 63 in-patients were analyzed who were culture positive for P. aeruginosa.Results: Majority of patients were aged above 40yrs with a male preponderance. Specimens were taken from patients who were diagnosed with bronchiectasis, pneumonia, COPD, bronchial asthma etc. Overall the organism was most sensitive to carbapenems (87.3%) followed by cefoperazone-sulbactam combination (85.7%). Sensitivity to ceftazidime and cefepime was equal (82.5%) and was more when compared to piperacillin-tazobactam (81.5%). Overall resistance rate was highest for fluoroquinolones (23.8%) followed by aztreonam (22.2%).Conclusions: Hence we would like to recommend cefoperazone-sulbactam as the preferred antipseudomonal agent and carbapenems as reserved drugs in treating pseudomonal lung infections. Use of fluoroquinolones and aztreonam as monotherapy in resistant P. aeruginosa infections should be restricted.

scholarly journals Could Azithromycin Be Part of Pseudomonas aeruginosa Acute Pneumonia Treatment?

2021 ◽  
Vol 12 ◽  
Author(s):  
Anne-Gaëlle Leroy ◽  
Jocelyne Caillon ◽  
Nathalie Caroff ◽  
Alexis Broquet ◽  
Stéphane Corvec ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Trials ◽  
Respiratory Infections ◽  
Direct Interaction ◽  
Membered Ring ◽  
Careful Examination ◽  
Major Interest ◽  
Acute Pneumonia

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including Pseudomonas aeruginosa (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted in vitro, these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. In vitro and in vivo studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.

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