Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide

Colistin is an important cationic antimicrobial peptide (CAMP) in the fight against Pseudomonas aeruginosa infection in cystic fibrosis (CF) lungs. The effects of subinhibitory concentrations of colistin on gene expression in P. aeruginosa were investigated by transcriptome and functional genomic approaches. Analysis revealed altered expression of 30 genes representing a variety of pathways associated with virulence and bacterial colonization in chronic infection. These included response to osmotic stress, motility, and biofilm formation, as well as genes associated with LPS modification and quorum sensing (QS). Most striking was the upregulation of Pseudomonas quinolone signal (PQS) biosynthesis genes, including pqsH, pqsB and pqsE, and the phenazine biosynthesis operon. Induction of this central component of the QS network following exposure to subinhibitory concentrations of colistin may represent a switch to a more robust population, with increased fitness in the competitive environment of the CF lung.

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Development and preclinical testing of a novel antimicrobial peptide to treat Pseudomonas aeruginosa-induced lung infections

Postdoc Journal ◽

10.14304/ffc2016proceedings.07 ◽

2016 ◽

Author(s):

Magnoni ML et al

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Peptide ◽

Preclinical Testing ◽

Lung Infections

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The sensor kinase PhoQ mediates virulence in Pseudomonas aeruginosa

Microbiology ◽

10.1099/mic.0.024554-0 ◽

2009 ◽

Vol 155 (3) ◽

pp. 699-711 ◽

Cited By ~ 64

Author(s):

W. James Gooderham ◽

Shaan L. Gellatly ◽

François Sanschagrin ◽

Joseph B. McPhee ◽

Manjeet Bains ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Regulatory System ◽

Polymyxin B ◽

Lung Epithelial Cells ◽

Cationic Antimicrobial Peptide ◽

Gram Negative ◽

Fold Reduction ◽

Lung Infections ◽

Antimicrobial Peptide Resistance ◽

Opportunistic Human Pathogen

Pseudomonas aeruginosa is a ubiquitous environmental Gram-negative bacterium that is also a major opportunistic human pathogen in nosocomial infections and cystic fibrosis chronic lung infections. PhoP-PhoQ is a two-component regulatory system that has been identified as essential for virulence and cationic antimicrobial peptide resistance in several other Gram-negative bacteria. This study demonstrated that mutation of phoQ caused reduced twitching motility, biofilm formation and rapid attachment to surfaces, 2.2-fold reduced cytotoxicity to human lung epithelial cells, substantially reduced lettuce leaf virulence, and a major, 10 000-fold reduction in competitiveness in chronic rat lung infections. Microarray analysis revealed that PhoQ controlled the expression of many genes consistent with these phenotypes and with its known role in polymyxin B resistance. It was also demonstrated that PhoQ controls the expression of many genes outside the known PhoP regulon.

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Highly efficient nanomedicine from cationic antimicrobial peptide-protected Ag nanoclusters

Journal of Materials Chemistry B ◽

10.1039/d0tb02267e ◽

2021 ◽

Author(s):

Zhikai Ye ◽

Haishuang Zhu ◽

Shan Zhang ◽

Jing Li ◽

Jin Wang ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Biological Systems ◽

Cationic Antimicrobial Peptide ◽

Highly Efficient ◽

Antimicrobial Efficiency ◽

Ag Nanoclusters ◽

Fine Tune

Designing the homogeneous assembly of the bio–nano interface to fine-tune the interactions between the nanoprobes and biological systems is of prime importance to improve the antimicrobial efficiency of nanomedicines.

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The Impact of an Efflux Pump Inhibitor on the Activity of Free and Liposomal Antibiotics against Pseudomonas aeruginosa

Pharmaceutics ◽

10.3390/pharmaceutics13040577 ◽

2021 ◽

Vol 13 (4) ◽

pp. 577

Author(s):

Douweh Leyla Gbian ◽

Abdelwahab Omri

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Antimicrobial Activities ◽

Dilution Method ◽

Efflux Pump Inhibitor ◽

Signal Production ◽

Lung Infections ◽

The Impact ◽

Microbroth Dilution

The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4–32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients.

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Insights into the Action Mechanism of the Antimicrobial Peptide Lasioglossin III

International Journal of Molecular Sciences ◽

10.3390/ijms22062857 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2857

Author(s):

Filomena Battista ◽

Rosario Oliva ◽

Pompea Del Vecchio ◽

Roland Winter ◽

Luigi Petraccone

Keyword(s):

Antimicrobial Peptide ◽

Gram Negative Bacteria ◽

Lipid Domains ◽

Action Mechanism ◽

Cationic Antimicrobial Peptide ◽

Intracellular Targeting ◽

Gel Retardation Assay ◽

Charged Membrane ◽

Intracellular Target ◽

Anionic Lipids

Lasioglossin III (LL-III) is a cationic antimicrobial peptide derived from the venom of the eusocial bee Lasioglossum laticeps. LL-III is extremely toxic to both Gram-positive and Gram-negative bacteria, and it exhibits antifungal as well as antitumor activity. Moreover, it shows low hemolytic activity, and it has almost no toxic effects on eukaryotic cells. However, the molecular basis of the LL-III mechanism of action is still unclear. In this study, we characterized by means of calorimetric (DSC) and spectroscopic (CD, fluorescence) techniques its interaction with liposomes composed of a mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-rac-phosphoglycerol (POPG) lipids as a model of the negatively charged membrane of pathogens. For comparison, the interaction of LL-III with the uncharged POPC liposomes was also studied. Our data showed that LL-III preferentially interacted with anionic lipids in the POPC/POPG liposomes and induces the formation of lipid domains. Furthermore, the leakage experiments showed that the peptide could permeabilize the membrane. Interestingly, our DSC results showed that the peptide-membrane interaction occurs in a non-disruptive manner, indicating an intracellular targeting mode of action for this peptide. Consistent with this hypothesis, our gel-retardation assay experiments showed that LL-III could interact with plasmid DNA, suggesting a possible intracellular target.

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