Evaluation of Pseudomonas aeruginosa pathogenesis and therapeutics in military‐relevant animal infection models

Apmis ◽  
2021 ◽  
Author(s):  
Alexander G. Bobrov ◽  
Derese Getnet ◽  
Brett Swierczewski ◽  
Anna Jacobs ◽  
Maria Medina‐Rojas ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Infection Models ◽  
Animal Infection

scholarly journals Impact of n-6 Polyunsaturated Fatty Acids on Growth of Multidrug-Resistant Pseudomonas aeruginosa: Interactions with Amikacin and Ceftazidime

2000 ◽  
Vol 44 (8) ◽  
pp. 2187-2189 ◽  
Author(s):  
E. J. Giamarellos-Bourboulis ◽  
P. Grecka ◽  
A. Dionyssiou-Asteriou ◽  
H. Giamarellou
Keyword(s):  
Fatty Acids ◽  
Pseudomonas Aeruginosa ◽  
Arachidonic Acid ◽  
Experimental Infection ◽  
Multidrug Resistant ◽  
Gamma Linolenic Acid ◽  
Infection Models ◽  
Over Time ◽  
In Vitro Interactions

ABSTRACT Twenty-six multidrug-resistant Pseudomonas aeruginosaisolates were exposed over time to 300 μg of gamma-linolenic acid or arachidonic acid per ml or to the combination of both acids at 150 μg/ml each with ceftazidime and amikacin with or without albumin to observe the in vitro interactions of the antibiotics. Antibiotics and albumin were applied at their levels found in serum. Synergy between acids and antibiotics was found against 13 isolates, and it was expressed after 5 h of growth in the presence of albumin. The results indicate that further application in experimental infection models is merited.

scholarly journals Effects of Antibiotics on Quorum Sensing in Pseudomonas aeruginosa

2008 ◽  
Vol 52 (10) ◽  
pp. 3648-3663 ◽  
Author(s):  
Mette E. Skindersoe ◽  
Morten Alhede ◽  
Richard Phipps ◽  
Liang Yang ◽  
Peter O. Jensen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factor ◽  
Dna Microarrays ◽  
Underlying Mechanism ◽  
Homoserine Lactone ◽  
Reverse Transcription Pcr ◽  
Animal Infection ◽  
Beneficial Action ◽  
Severe Infections

ABSTRACT During infection, Pseudomonas aeruginosa employs bacterial communication (quorum sensing [QS]) to coordinate the expression of tissue-damaging factors. QS-controlled gene expression plays a pivotal role in the virulence of P. aeruginosa, and QS-deficient mutants cause less severe infections in animal infection models. Treatment of cystic fibrosis (CF) patients chronically infected with P. aeruginosa with the macrolide antibiotic azithromycin (AZM) has been demonstrated to improve the clinical outcome. Several studies indicate that AZM may accomplish its beneficial action in CF patients by impeding QS, thereby reducing the pathogenicity of P. aeruginosa. This led us to investigate whether QS inhibition is a common feature of antibiotics. We present the results of a screening of 12 antibiotics for their QS-inhibitory activities using a previously described QS inhibitor selector 1 strain. Three of the antibiotics tested, AZM, ceftazidime (CFT), and ciprofloxacin (CPR), were very active in the assay and were further examined for their effects on QS-regulated virulence factor production in P. aeruginosa. The effects of the three antibiotics administered at subinhibitory concentrations were investigated by use of DNA microarrays. Consistent results from the virulence factor assays, reverse transcription-PCR, and the DNA microarrays support the finding that AZM, CFT, and CPR decrease the expression of a range of QS-regulated virulence factors. The data suggest that the underlying mechanism may be mediated by changes in membrane permeability, thereby influencing the flux of N-3-oxo-dodecanoyl-l-homoserine lactone.

scholarly journals Allele- and Tir-Independent Functions of Intimin in Diverse Animal Infection Models

2012 ◽  
Vol 3 ◽  
Author(s):  
Emily M. Mallick ◽  
Michael J. Brady ◽  
Steven A. Luperchio ◽  
Vijay K. Vanguri ◽  
Loranne Magoun ◽  
...  
Keyword(s):  
Infection Models ◽  
Independent Functions ◽  
Animal Infection

scholarly journals NirA Is an Alternative Nitrite Reductase from Pseudomonas aeruginosa with Potential as an Antivirulence Target

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Samuel Fenn ◽  
Jean-Frédéric Dubern ◽  
Cristina Cigana ◽  
Maura De Simone ◽  
James Lazenby ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nitrite Reductase ◽  
Disease Models ◽  
Attractive Alternative ◽  
Dependent Manner ◽  
Content Type ◽  
Isogenic Mutant ◽  
Virulence Traits ◽  
Infection Models

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa produces an arsenal of virulence factors causing a wide range of diseases in multiple hosts and is difficult to eradicate due to its intrinsic resistance to antibiotics. With the antibacterial pipeline drying up, antivirulence therapy has become an attractive alternative strategy to the traditional use of antibiotics to treat P. aeruginosa infections. To identify P. aeruginosa genes required for virulence in multiple hosts, a random library of Tn5 mutants in strain PAO1-L was previously screened in vitro for those showing pleiotropic effects in the production of virulence phenotypes. Using this strategy, we identified a Tn5 mutant with an insertion in PA4130 showing reduced levels of a number of virulence traits in vitro. Construction of an isogenic mutant in this gene presented results similar to those for the Tn5 mutant. Furthermore, the PA4130 isogenic mutant showed substantial attenuation in disease models of Drosophila melanogaster and Caenorhabditis elegans as well as reduced toxicity in human cell lines. Mice infected with this mutant demonstrated an 80% increased survival rate in acute and agar bead lung infection models. PA4130 codes for a protein with homology to nitrite and sulfite reductases. Overexpression of PA4130 in the presence of the siroheme synthase CysG enabled its purification as a soluble protein. Methyl viologen oxidation assays with purified PA4130 showed that this enzyme is a nitrite reductase operating in a ferredoxin-dependent manner. The preference for nitrite and production of ammonium revealed that PA4130 is an ammonia:ferredoxin nitrite reductase and hence was named NirA. IMPORTANCE The emergence of widespread antimicrobial resistance has led to the need for development of novel therapeutic interventions. Antivirulence strategies are an attractive alternative to classic antimicrobial therapy; however, they require identification of new specific targets which can be exploited in drug discovery programs. The host-specific nature of P. aeruginosa virulence adds complexity to the discovery of these types of targets. Using a sequence of in vitro assays and phylogenetically diverse in vivo disease models, we have identified a PA4130 mutant with reduced production in a number of virulence traits and severe attenuation across all infection models tested. Characterization of PA4130 revealed that it is a ferredoxin-nitrite reductase and hence was named NirA. These results, together with attenuation of nirA mutants in different clinical isolates, high level conservation of its gene product in P. aeruginosa genomes, and the lack of orthologues in human genomes, make NirA an attractive antivirulence target.

scholarly journals 73 Evaluation of efficacy of P0L7001 against Pseudomonas aeruginosa in lung infection models

2012 ◽  
Vol 11 ◽  
pp. S75
Author(s):  
A. Bragonzi ◽  
F. Bernardini ◽  
M. Facchini ◽  
C. Cigana ◽  
B. Alcala-Franco ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Lung Infection ◽  
Infection Models

scholarly journals The development of animal infection models and antifungal efficacy assays against clinical isolates ofTrichosporon asahii,T. asteroidesandT. inkin

Virulence ◽  
2015 ◽  
Vol 6 (5) ◽  
pp. 476-486 ◽  
Author(s):  
Marçal Mariné ◽  
Vinicius Leite Pedro Bom ◽  
Patricia Alves de Castro ◽  
Lizziane Kretli Winkelstroter ◽  
Leandra Naira Ramalho ◽  
...  
Keyword(s):  
Clinical Isolates ◽  
Infection Models ◽  
Animal Infection ◽  
Antifungal Efficacy

scholarly journals Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa

2008 ◽  
Vol 53 (1) ◽  
pp. 46-56 ◽  
Author(s):  
Jürgen B. Bulitta ◽  
Neang S. Ly ◽  
Jenny C. Yang ◽  
Alan Forrest ◽  
William J. Jusko ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Predictive Performance ◽  
Pkpd Model ◽  
Infection Models ◽  
The Mean ◽  
Inoculum Effect ◽  
Successful Replication ◽  
Time Kill ◽  
The Impact

ABSTRACT Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic/pharmacodynamic (PKPD) mathematical model accommodating a range of CFUo. Time-kill experiments using ceftazidime at seven concentrations up to 128 mg/liter (MIC, 2 mg/liter) were performed in duplicate against P. aeruginosa PAO1 at five CFUo from 105 to 109 CFU/ml. Samples were collected over 24 h and fit by candidate models in NONMEM VI and S-ADAPT 1.55 (all data were comodeled). External model qualification integrated data from eight previously published studies. Ceftazidime displayed approximately 3 to 4 log10 CFU/ml net killing at 106.2 CFUo and concentrations of 4 mg/liter (or higher), less than 1.6 log10 CFU/ml killing at 107.3 CFUo, and no killing at 108.0 CFUo for concentrations up to 128 mg/liter. The proposed mechanism-based model successfully described the inoculum effect and the concentration-independent lag time of killing. The mean generation time was 28.3 min. The effect of an autolysin was assumed to inhibit successful replication. Ceftazidime concentrations of 0.294 mg/liter stimulated the autolysin effect by 50%. The model was predictive in the internal cross-validation and had excellent in silico predictive performance for published studies of P. aeruginosa ATCC 27853 for various CFUo. The proposed PKPD model successfully described and predicted the pronounced inoculum effect of ceftazidime in vitro and integrated data from eight literature studies to support translation from time-kill experiments to in vitro infection models.

scholarly journals Identification of Mycobacterium tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening

2004 ◽  
Vol 72 (9) ◽  
pp. 5315-5321 ◽  
Author(s):  
Katherine B. Hisert ◽  
Meghan A. Kirksey ◽  
James E. Gomez ◽  
Alexandra O. Sousa ◽  
Jeffery S. Cox ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Genetic Studies ◽  
Immunodeficient Mice ◽  
Immune Mechanisms ◽  
Infection Models ◽  
Animal Infection ◽  
Ifn Γ ◽  
Bacterial Genes ◽  
Oxide Synthase ◽  
Deficient Mice

ABSTRACT Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-γ) in resistance to TB. IFN-γ activates a large number of antimicrobial pathways. Three of these IFN-γ-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide synthase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we have identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-γ-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-γ-dependent immune mechanisms other than iNOS.

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