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

Chen, C.; Deslouches, Berthony; Montelaro, Ronald C.; Di, Y. Peter

doi:10.1016/j.cmi.2017.08.029

Cited by 38 publications

(44 citation statements)

References 29 publications

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“…As a primary characterization of the cytotoxic property, we compared the two peptides for hemolytic activities using freshly isolated human erythrocytes. Both peptides show no detectable hemolytic activity at concentrations up to 100μM ( Fig 5 ), in contrast to the engineered AMP control WLBU2[ 31 , 33 , 40 , 41 ], which displayed up to 20% hemolysis.…”

Section: Resultsmentioning

confidence: 96%

“…To illustrate, we compared the hemolytic profile of the engineered AMP WLBU2, which is in advanced preclinical development, with that of α4 and α4M1. WLBU2 has been extensively characterized both in vitro and in vivo[ 30 , 33 – 35 , 40 , 41 , 49 – 52 ] . It displays broad-spectrum activity against the most common MDR bacteria known as ESKAPE pathogens[ 34 ] and outperforms the last-resort antibiotic colistin against these MDR clinical strains.…”

Section: Discussionmentioning

confidence: 99%

“…One particular motif, called α4, displays a helical structure. On closer examination, this domain appears to exhibit a cationic amphipathic structure similar to that of well-known natural AMPs[ 29 – 32 ], with a positive charge of 2. We hypothesized that the antimicrobial α4 motif of SPLUNC1 with the characteristic of natural antimicrobial peptides can be used as a novel standalone antibiofilm agent.…”

Section: Introductionmentioning

confidence: 90%

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Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus

Deslouches

Walton

et al. 2018

PLoS ONE

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SPLUNC1 is a multifunctional protein of the airway with antimicrobial properties. We previously reported that it displayed antibiofilm activities against P. aeruginosa. The goal of this study was to determine whether (1) the antibiofilm property is broad (including S. aureus, another prevalent organism in cystic fibrosis); (2) the α4 region is responsible for such activity; and (3), if so, this motif could be structurally optimized as an antimicrobial peptide with enhanced activities. We used S. aureus biofilm-prevention assays to determine bacterial biomass in the presence of SPLUNC1 and SPLUNC1Δα4 recombinant proteins, or SPLUNC1-derived peptides (α4 and α4M1), using the well-established crystal-violet biofilm detection assay. The SPLUNC1Δα4 showed markedly reduced biofilm prevention compared to the parent protein. Surprisingly, the 30-residue long α4 motif alone demonstrated minimal biofilm prevention activities. However, structural optimization of the α4 motif resulted in a modified peptide (α4M1) with significantly enhanced antibiofilm properties against methicillin–sensitive (MSSA) and–resistant (MRSA) S. aureus, including six different clinical strains of MRSA and the well-known USA300. Hemolytic activity was undetectable at up to 100μM for the peptides. The data warrant further investigation of α4-derived AMPs to explore the potential application of antimicrobial peptides to combat bacterial biofilm-related infections.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus

Deslouches

Walton

et al. 2018

PLoS ONE

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“…AMPs may also elicit an anti-infective host immune response and possess the ability to neutralize endotoxins, suggesting potential efficacy in septic shock [51,56,[96][97][98][99][100]. Further, their anti-biofilm properties may confer efficacy against infections associated with wounds, medical implants, and chronic respiratory illnesses [82,91,[101][102][103][104]. Antitumor properties also suggest a potential application against cancer [105].…”

Section: Introductionmentioning

confidence: 99%

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

et al. 2020

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The increasing rate of antibiotic resistance constitutes a global health crisis. Antimicrobial peptides (AMPs) have the property to selectively kill bacteria regardless of resistance to traditional antibiotics. However, several challenges (e.g., reduced activity in the presence of serum and lack of efficacy in vivo) to clinical development need to be overcome. In the last two decades, we have addressed many of those challenges by engineering cationic AMPs de novo for optimization under test conditions that typically inhibit the activities of natural AMPs, including systemic efficacy. We reviewed some of the most promising data of the last two decades in the context of the advancement of the field of helical AMPs toward clinical development.

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“…Antimicrobial peptides (AMPs) are a promising area of therapeutic agents with great potential as an alternative for conventional antibacterial therapies. Many have noted the potential application of AMPs and their synthetic analogues as antibiofilm agents [8][9][10][11][12][13][14][15]. These small cationic and amphipathic peptides function as the first line of defense for a variety of animals and plants and, as such, play a key role in both antimicrobial activity and immunomodulation.…”

Section: Introductionmentioning

confidence: 99%

The Addition of a Synthetic LPS-Targeting Domain Improves Serum Stability While Maintaining Antimicrobial, Antibiofilm, and Cell Stimulating Properties of an Antimicrobial Peptide

et al. 2020

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Multi-drug resistant (MDR) bacteria and their biofilms are a concern in veterinary and human medicine. Protegrin-1 (PG-1), a potent antimicrobial peptide (AMP) with antimicrobial and immunomodulatory properties, is considered a potential alternative for conventional antibiotics. AMPs are less stable and lose activity in the presence of physiological fluids, such as serum. To improve stability of PG-1, a hybrid peptide, SynPG-1, was designed. The antimicrobial and antibiofilm properties of PG-1 and the PG-1 hybrid against MDR pathogens was analyzed, and activity after incubation with physiological fluids was compared. The effects of these peptides on the IPEC-J2 cell line was also investigated. While PG-1 maintained some activity in 25% serum for 2 h, SynPG-1 was able to retain activity in the same condition for up to 24 h, representing a 12-fold increase in stability. Both peptides had some antibiofilm activity against Escherichia coli and Salmonella typhimurium. While both peptides prevented biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA), neither could destroy MRSA’s pre-formed biofilms. Both peptides maintained activity after incubation with trypsin and porcine gastric fluid, but not intestinal fluid, and stimulated IPEC-J2 cell migration. These findings suggest that SynPG-1 has much better serum stability while maintaining the same antimicrobial potency as PG-1.

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

Abstract: These promising results now establish a much lower minimum therapeutic dose of WLBU2 (a net gain of 80-fold) compared with the previously reported 4 mg/kg systemic minimum therapeutic dose, with significant implications for clinical development.

Cited by 38 publications

References 29 publications

Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus

Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

The Addition of a Synthetic LPS-Targeting Domain Improves Serum Stability While Maintaining Antimicrobial, Antibiofilm, and Cell Stimulating Properties of an Antimicrobial Peptide

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