scholarly journals Alleviation of Pseudomonas aeruginosa Infection by Propeptide-Mediated Inhibition of Protease IV

2021 ◽  
Author(s):  
Tae-Hyeon Kim ◽  
Xi-Hui Li ◽  
Joon-Hee Lee
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Pseudomonas Aeruginosa Infection ◽  
Protease Iv ◽  
Conventional Antibiotics

Pseudomonas aeruginosa is a highly antibiotic-resistant pathogen and is extremely difficult to treat. Instead of using conventional antibiotics, we attempted to alleviate P. aeruginosa infection using factors that P. aeruginosa itself produces naturally.

scholarly journals A Small Membrane Stabilizing Protein Critical to the Pathogenicity of Staphylococcus aureus

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Seána Duggan ◽  
Maisem Laabei ◽  
Alaa Abdulaziz Alnahari ◽  
Eóin C. O’Brien ◽  
Keenan A. Lacey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Iron Homeostasis ◽  
Control Strategies ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Promising Target ◽  
Significant Impairment ◽  
The Stability ◽  
Conventional Antibiotics ◽  
And Control

ABSTRACT Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.

scholarly journals Acidosis Potentiates the Host Proinflammatory Interleukin-1β Response to Pseudomonas aeruginosa Infection

2014 ◽  
Vol 82 (11) ◽  
pp. 4689-4697 ◽  
Author(s):  
Iviana M. Torres ◽  
Yash R. Patankar ◽  
Tamer B. Shabaneh ◽  
Emily Dolben ◽  
Deborah A. Hogan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Interleukin 1Β ◽  
Acidic Environment ◽  
Content Type ◽  
Inflammatory Damage ◽  
Pseudomonas Aeruginosa Infection ◽  
Peritonitis Model

ABSTRACTInfection byPseudomonas aeruginosa, and bacteria in general, frequently promotes acidification of the local microenvironment, and this is reinforced by pulmonary exertion and exacerbation. However, the consequence of an acidic environment on the host inflammatory response toP. aeruginosainfection is poorly understood. Here we report that the pivotal cellular and host proinflammatory interleukin-1β (IL-1β) response, which enables host clearance of the infection but can produce collateral inflammatory damage, is increased in response toP. aeruginosainfection within an acidic environment. Synergistic mechanisms that promote increased IL-1β release in response toP. aeruginosainfection in an acidic environment are increased pro-IL-1β induction and increased caspase-1 activity, the latter being dependent upon a functional type III secretion system of the bacteria and the NLRC4 inflammasome of the host. Using anin vivoperitonitis model, we have validated that the IL-1β inflammatory response is increased in mice in response toP. aeruginosainfection within an acidic microenvironment. These data reveal novel insights into the regulation and exacerbation of inflammatory responses toP. aeruginosa.

scholarly journals Novel Aminoglycoside-Tolerant Phoenix Colony Variants of Pseudomonas aeruginosa

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Devin Sindeldecker ◽  
Kelly Moore ◽  
Anthony Li ◽  
Daniel J. Wozniak ◽  
Matthew Anderson ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Calcium Sulfate ◽  
Bacterial Pathogen ◽  
Wild Type ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Persistent Infections ◽  
High Concentrations ◽  
First Time ◽  
Very High

ABSTRACT Pseudomonas aeruginosa is an opportunistic bacterial pathogen and is known to produce biofilms. We previously showed the emergence of colony variants in the presence of tobramycin-loaded calcium sulfate beads. In this study, we characterized the variant colonies, which survived the antibiotic treatment, and identified three distinct phenotypes—classically resistant colonies, viable but nonculturable colonies (VBNC), and phoenix colonies. Phoenix colonies, described here for the first time, grow out of the zone of clearance of antibiotic-loaded beads from lawn biofilms while there are still very high concentrations of antibiotic present, suggesting an antibiotic-resistant phenotype. However, upon subculturing of these isolates, phoenix colonies return to wild-type levels of antibiotic susceptibility. Compared with the wild type, phoenix colonies are morphologically similar aside from a deficiency in green pigmentation. Phoenix colonies do not recapitulate the phenotype of any previously described mechanisms of resistance, tolerance, or persistence and, thus, form a novel group with their own phenotype. Growth under anaerobic conditions suggests that an alternative metabolism could lead to the formation of phoenix colonies. These findings suggest that phoenix colonies could emerge in response to antibiotic therapies and lead to recurrent or persistent infections, particularly within biofilms where microaerobic or anaerobic environments are present.

scholarly journals Silver Oxynitrate, an Unexplored Silver Compound with Antimicrobial and Antibiofilm Activity

2015 ◽  
Vol 59 (7) ◽  
pp. 4031-4039 ◽  
Author(s):  
Joe A. Lemire ◽  
Lindsay Kalan ◽  
Alexandru Bradu ◽  
Raymond J. Turner
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antibiofilm Activity ◽  
Metal Compounds ◽  
Antibiotic Resistant ◽  
Content Type ◽  
New Antibiotics ◽  
Silver Compound ◽  
Therapeutic Compound

ABSTRACTHistorically it has been accepted, and recent research has established, that silver (Ag) is an efficacious antimicrobial agent. A dwindling pipeline of new antibiotics, combined with an increase in the number of antibiotic-resistant infections, is bringing Ag to the fore as a therapeutic compound to treat infectious diseases. Currently, many formulations of Ag are being deployed for commercial and medical purposes, with various degrees of effectiveness at killing microbial cells. Here, we evaluated the antimicrobial and antibiofilm capacity of our lead compound, silver oxynitrate [Ag(Ag3O4)2NO3or Ag7NO11], against other metal compounds with documented antimicrobial activity, including Ag2SO4, AgNO3, silver sulfadiazine (AgSD), AgO, Ag2O, and CuSO4. Our findings reveal that Ag7NO11eradicates biofilm and planktonic populations ofPseudomonas aeruginosa,Escherichia coli,Staphylococcus aureus, uropathogenicEscherichia coli(UPEC), fluoroquinolone-resistantPseudomonas aeruginosa(FQRP), and methicillin-resistantStaphylococcus aureus(MRSA) at lower concentrations than those of the other tested metal salts. Altogether, our results demonstrate that Ag7NO11has an enhanced efficacy for the treatment of biofilm-forming pathogens.

scholarly journals Dynamics of Mutator and Antibiotic-Resistant Populations in a Pharmacokinetic/Pharmacodynamic Model of Pseudomonas aeruginosa Biofilm Treatment

2011 ◽  
Vol 55 (11) ◽  
pp. 5230-5237 ◽  
Author(s):  
María D. Macià ◽  
José L. Pérez ◽  
Soeren Molin ◽  
Antonio Oliver
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Laser Scanning ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Resistance Development ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants

ABSTRACTBiofilm growth, antibiotic resistance, and mutator phenotypes are key components of chronic respiratory infections byPseudomonas aeruginosain cystic fibrosis patients. We examined the dynamics of mutator and antibiotic-resistant populations inP. aeruginosaflow-cell biofilms, using fluorescently tagged PAO1 and PAOMS (mutator [mutS] derivative) strains. Two-day-old biofilms were treated with ciprofloxacin (CIP) for 4 days (t4) at 2 μg/ml, which correlated with the mutant prevention concentration (MPC) and provided an AUC/MIC ratio of 384 that should predict therapeutic success. Biofilms were monitored by confocal laser scanning microscopy (CLSM), and the numbers of viable cells and resistant mutants (4- and 16-fold MICs) were determined. Despite optimized pharmacokinetic/pharmacodynamic (PK/PD) parameters, CIP treatment did not suppress resistance development inP. aeruginosabiofilms. One-step resistant mutants (MexCD-OprJ or MexEF-OprN overexpression) were selected for both strains, while two-step resistant mutants (additional GyrA or GyrB mutation) were readily selected only from the mutator strain. CLSM analysis of competition experiments revealed that PAOMS, even when inoculated at a 0.01 proportion, took over the whole biofilm after only 2 days of CIP treatment outnumbering PAO1 by 3 log at t4. Our results show that mutational mechanisms play a major role in biofilm antibiotic resistance and that theoretically optimized PK/PD parameters fail to suppress resistance development, suggesting that the increased antibiotic tolerance driven by the special biofilm physiology and architecture may raise the effective MPC, favoring gradual mutational resistance development, especially in mutator strains. Moreover, the amplification of mutator populations under antibiotic treatment by coselection with resistance mutations is for the first time demonstratedin situforP. aeruginosabiofilms.

scholarly journals Antimicrobial Peptoids Are Effective against Pseudomonas aeruginosa Biofilms

2011 ◽  
Vol 55 (6) ◽  
pp. 3054-3057 ◽  
Author(s):  
Rinki Kapoor ◽  
Mayken W. Wadman ◽  
Michelle T. Dohm ◽  
Ann M. Czyzewski ◽  
Alfred M. Spormann ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Cell Viability ◽  
Pulmonary Infections ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTThe resistance of biofilms to conventional antibiotics complicates the treatment of chronic cystic fibrosis (CF). We investigated the effects of peptoids, peptides, and conventional antibiotics on the biomass and cell viability withinPseudomonas aeruginosabiofilms. At their MICs, peptoids 1 and 1-C134mercaused maximum reductions in biomass and cell viability, respectively. These results suggest that peptoids of this class could be worth exploring for the treatment of pulmonary infections occurring in CF patients.

scholarly journals Candida albicans Airway Exposure Primes the Lung Innate Immune Response against Pseudomonas aeruginosa Infection through Innate Lymphoid Cell Recruitment and Interleukin-22-Associated Mucosal Response

2013 ◽  
Vol 82 (1) ◽  
pp. 306-315 ◽  
Author(s):  
Jean Baptiste Mear ◽  
Philippe Gosset ◽  
Eric Kipnis ◽  
Emmanuel Faure ◽  
Rodrigue Dessein ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Candida Albicans ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Lymphoid Cells ◽  
Content Type ◽  
Cell Recruitment ◽  
Interleukin 22 ◽  
Cellular Source ◽  
Pseudomonas Aeruginosa Infection

ABSTRACTPseudomonas aeruginosaandCandida albicansare two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated thatC. albicansairway exposure protected againstP. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated withC. albicans-induced protection. Airway exposure byC. albicansled to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolishedC. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti-CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival afterP. aeruginosachallenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection againstP. aeruginosa-induced lung injury. This cytokine may represent a clinical target inPseudomonas aeruginosa-induced lung injury.

scholarly journals Mechanism of Enhanced Activity of Liposome-Entrapped Aminoglycosides against Resistant Strains of Pseudomonas aeruginosa

2006 ◽  
Vol 50 (6) ◽  
pp. 2016-2022 ◽  
Author(s):  
Clement Mugabe ◽  
Majed Halwani ◽  
Ali O. Azghani ◽  
Robert M. Lafrenie ◽  
Abdelwahab Omri
Keyword(s):  
Flow Cytometry ◽  
Pseudomonas Aeruginosa ◽  
Outer Membrane ◽  
Fusion Rate ◽  
Bacterial Cells ◽  
Antibiotic Resistant ◽  
Transmission Electron ◽  
Resistant Strains ◽  
Conventional Antibiotics ◽  
Liposomal Drugs

ABSTRACT Pseudomonas aeruginosa is inherently resistant to most conventional antibiotics. The mechanism of resistance of this bacterium is mainly associated with the low permeability of its outer membrane to these agents. We sought to assess the bactericidal efficacy of liposome-entrapped aminoglycosides against resistant clinical strains of P. aeruginosa and to define the mechanism of liposome-bacterium interactions. Aminoglycosides were incorporated into liposomes, and the bactericidal efficacies of both free and liposomal drugs were evaluated. To define the mechanism of liposome-bacterium interactions, transmission electron microscopy (TEM), flow cytometry, lipid mixing assay, and immunocytochemistry were employed. Encapsulation of aminoglycosides into liposomes significantly increased their antibacterial activity against the resistant strains used in this study (MICs of ≥32 versus ≤8 μg/ml). TEM observations showed that liposomes interact intimately with the outer membrane of P. aeruginosa, leading to the membrane deformation. The flow cytometry and lipid mixing assays confirmed liposome-bacterial membrane fusion, which increased as a function of incubation time. The maximum fusion rate was 54.3% ± 1.5% for an antibiotic-sensitive strain of P. aeruginosa and 57.8% ± 1.9% for a drug-resistant strain. The fusion between liposomes and P. aeruginosa significantly enhanced the antibiotics' penetration into the bacterial cells (3.2 ± 2.3 versus 24.2 ± 6.2 gold particles/bacterium, P ≤ 0.001). Our data suggest that liposome-entrapped antibiotics could successfully resolve infections caused by antibiotic-resistant P. aeruginosa through an enhanced mechanism of drug entry into the bacterial cells.

scholarly journals Inhibition of Biofilm Formation by Esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

2012 ◽  
Vol 56 (8) ◽  
pp. 4360-4364 ◽  
Author(s):  
Vandana Singh ◽  
Vaneet Arora ◽  
M. Jahangir Alam ◽  
Kevin W. Garey
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Growth ◽  
Biofilm Formation ◽  
Antimicrobial Properties ◽  
Antibiofilm Activity ◽  
Biofilm Growth ◽  
Content Type ◽  
Conventional Antibiotics ◽  
And Staphylococcus Aureus

ABSTRACTStaphylococcus aureusandPseudomonas aeruginosaare common nosocomial pathogens responsible for biofilm-associated infections. Proton pump inhibitors (PPI), such as esomeprazole, may have novel antimicrobial properties. The objective of this study was to assess whether esomeprazole prevents sessile bacterial growth and biofilm formation and whether it may have synergistic killing effects with standard antibiotics. The antibiofilm activity of esomeprazole at 0.25 mM was tested against two strains each ofS. aureusandP. aeruginosa. Bacterial biofilms were prepared using a commercially available 96-peg-plate Calgary biofilm device. Sessile bacterial CFU counts and biomass were assessed during 72 hours of esomeprazole exposure. The killing activities after an additional 24 hours of vancomycin (againstS. aureus) and meropenem (againstP. aeruginosa) treatment with or without preexposure to esomeprazole were also assessed by CFU and biomass analyses.P. aeruginosaandS. aureusstrains exposed to esomeprazole displayed decreased sessile bacterial growth and biomass (P< 0.001, each parameter). After 72 h of exposure, there was a 1-log10decrease in the CFU/ml of esomeprazole-exposedP. aeruginosaandS. aureusstrains compared to controls (P< 0.001). After 72 h of exposure, measured absorbance was 100% greater inP. aeruginosacontrol strains than in esomeprazole-exposed strains (P< 0.001). Increased killing and decreased biomass were observed for esomeprazole-treated bacteria compared to untreated controls exposed to conventional antibiotics (P< 0.001, each parameter). Reduced biofilm growth after 24 h was visibly apparent by light micrographs forP. aeruginosaandS. aureusisolates exposed to esomeprazole compared to untreated controls. In conclusion, esomeprazole demonstrated an antibiofilm effect against biofilm-producingS. aureusandP. aeruginosa.

scholarly journals Effects of 14-Alpha-Lipoyl Andrographolide on Quorum Sensing in Pseudomonas aeruginosa

2012 ◽  
Vol 56 (12) ◽  
pp. 6088-6094 ◽  
Author(s):  
Li Ma ◽  
Xiangyang Liu ◽  
Haihua Liang ◽  
Yizhou Che ◽  
Caixia Chen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
Homoserine Lactone ◽  
Inhibitory Effect ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTInPseudomonas aeruginosa, the quorum-sensing (QS) system is closely related to biofilm formation. We previously demonstrated that 14-alpha-lipoyl andrographolide (AL-1) has synergistic effects on antibiofilm and antivirulence factors (pyocyanin and exopolysaccharide) ofP. aeruginosawhen combined with conventional antibiotics, while it has little inhibitory effect on its growth. However, its molecular mechanism remains elusive. Here we investigated the effect of AL-1 on QS systems, especially the Las and Rhl systems. This investigation showed that AL-1 can inhibit LasR–3-oxo-C12-homoserine lactone (HSL) interactions and repress the transcriptional level of QS-regulated genes. Reverse transcription (RT)-PCR data showed that AL-1 significantly reduced the expression levels oflasR,lasI,rhlR, andrhlIin a dose-dependent manner. AL-1 not only decreased the expression level of Psl, which is positively regulated by the Las system, but also increased the level of secretion of ExoS, which is negatively regulated by the Rhl system, indicating that AL-1 has multiple effects on both the Las and Rhl systems. It is no wonder that AL-1 showed synergistic effects with other antimicrobial agents in the treatment ofP. aeruginosainfections.

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