De novo-derived cationic antimicrobial peptide activity in a murine model of Pseudomonas aeruginosa bacteraemia

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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Activity of the De Novo Engineered Antimicrobial Peptide WLBU2 against Pseudomonas aeruginosa in Human Serum and Whole Blood: Implications for Systemic Applications

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.8.3208-3216.2005 ◽

2005 ◽

Vol 49 (8) ◽

pp. 3208-3216 ◽

Cited By ~ 99

Author(s):

Berthony Deslouches ◽

Kazi Islam ◽

Jodi K. Craigo ◽

Shruti M. Paranjape ◽

Ronald C. Montelaro ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Peptide ◽

Human Serum ◽

Whole Blood ◽

De Novo ◽

Host Cells ◽

Resistant Bacteria ◽

Infection Model ◽

Bacterial Killing ◽

Biologically Relevant

ABSTRACT Cationic amphipathic peptides have been extensively investigated as a potential source of new antimicrobials that can complement current antibiotic regimens in the face of emerging drug-resistant bacteria. However, the suppression of antimicrobial activity under certain biologically relevant conditions (e.g., serum and physiological salt concentrations) has hampered efforts to develop safe and effective antimicrobial peptides for clinical use. We have analyzed the activity and selectivity of the human peptide LL37 and the de novo engineered antimicrobial peptide WLBU2 in several biologically relevant conditions. The host-derived synthetic peptide LL37 displayed high activity against Pseudomonas aeruginosa but demonstrated staphylococcus-specific sensitivity to NaCl concentrations varying from 50 to 300 mM. Moreover, LL37 potency was variably suppressed in the presence of 1 to 6 mM Mg2+ and Ca2+ ions. In contrast, WLBU2 maintained its activity in NaCl and physiologic serum concentrations of Mg2+ and Ca2+. WLBU2 is able to kill P. aeruginosa (106 CFU/ml) in human serum, with a minimum bactericidal concentration of <9 μM. Conversely, LL37 is inactive in the presence of human serum. Bacterial killing kinetic assays in serum revealed that WLBU2 achieved complete bacterial killing in 20 min. Consistent with these results was the ability of WLBU2 (15 to 20 μM) to eradicate bacteria from ex vivo samples of whole blood. The selectivity of WLBU2 was further demonstrated by its ability to specifically eliminate P. aeruginosa in coculture with human monocytes or skin fibroblasts without detectable adverse effects to the host cells. Finally, WLBU2 displayed potent efficacy against P. aeruginosa in an intraperitoneal infection model using female Swiss Webster mice. These results establish a potential application of WLBU2 in the treatment of bacterial sepsis.

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Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia

Clinical Microbiology and Infection ◽

10.1016/j.cmi.2017.08.029 ◽

2018 ◽

Vol 24 (5) ◽

pp. 547.e1-547.e8 ◽

Cited By ~ 13

Author(s):

C. Chen ◽

B. Deslouches ◽

R.C. Montelaro ◽

Y.P. Di

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Peptide ◽

Murine Model

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D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection

Frontiers in Chemistry ◽

10.3389/fchem.2017.00040 ◽

2017 ◽

Vol 5 ◽

Cited By ~ 6

Author(s):

Mario Mardirossian ◽

Arianna Pompilio ◽

Margherita Degasperi ◽

Giulia Runti ◽

Sabrina Pacor ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Peptide ◽

Murine Model ◽

Lung Infection

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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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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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