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Innate defense regulators (IDRs) are synthetic host-defense peptides (HDPs) with broad-spectrum anti-infective properties, including immunomodulatory, anti-biofilm and direct antimicrobial activities. A lack of pharmacokinetic data about these peptides hinders their development and makes it challenging to fully understand how they work in vivo since their mechanism of action is dependent on tissue concentrations of the peptide. Here, we set out to define in detail the pharmacokinetics of a well-characterized IDR molecule, IDR-1018. To make the peptide traceable, it was radiolabeled with the long-lived gamma-emitting isotope gallium-67. After a series of bench-top characterizations, the radiotracer was administered to healthy mice intravenously (IV) or subcutaneously (SQ) at various dose levels (2.5-13 mg/kg). Nuclear imaging and ex-vivo biodistributions were used to quantify organ and tissue uptake of the radiotracer over time. When administered as an IV bolus, the distribution profile of the radiotracer changed as the dose was escalated. At 2.5 mg/kg, the peptide was well-tolerated, poorly circulated in the blood and was cleared predominantly by the reticuloendothelial system. Higher doses (7 and 13 mg/kg) as an IV bolus were almost immediately lethal due to respiratory arrest; significant lung uptake of the radiotracer was observed from nuclear scans of these animals, and histological examination found extensive damage to the pulmonary vasculature and alveoli. When administered SQ at a dose of 3 mg/kg, radiolabeled IDR-1018 was rapidly absorbed from the site of injection and predominately cleared renally. Apart from the SQ injection site, no other tissue had a concentration above the minimum inhibitory concentration that would enable this peptide to exert direct antimicrobial effects against most pathogenic bacteria. Tissue concentrations were sufficient, however, to disrupt microbial biofilms and alter the host immune response. Overall, this study demonstrated that the administration of synthetic IDR peptide in vivo is best suited to local administration which avoids some of the issues associated with peptide toxicity that are observed when administered systemically by IV injection, an issue that will have to be addressed through formulation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EFH and REWH have invented and filed for patent protection on IDR-1018 and related peptide sequences. This patent has been assigned to their employer, the University of British Columbia, and has been licensed to ABT Innovations Inc., in which both have an ownership position. ABT Innovations Inc. is a subsidiary of ASEP Medical Holdings Inc. EFH is employed by ASEP and receives salary while REWH holds an executive position and is on the Board of ASEP. TVFE, CB, DP, CRR, KS and UOH report no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo- N -substituted glycines) resist proteolytic digestion and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here, we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic AMPs designed to self-assemble and two nonassembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small-angle X-ray scattering; some adopt helical bundles, while others form core-shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, antibiofilm activity in vitro in media, under host-mimicking conditions and antiabscess activity in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better-suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm, and antiabscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections relevant to clinical medicine.

Host defence peptides (HDPs) are integral components of innate immunity across all living organisms. These peptides can exert direct antibacterial effects, targeting planktonic cells (referred to as antimicrobial peptides), and exhibit antibiofilm (referred to as antibiofilm peptides), antiviral, antifungal and host-directed immunomodulatory activities. In this Review, we discuss how the complex functional attributes of HDPs provide many opportunities for the development of antimicrobial therapeutics, focusing particularly on their emerging antibiofilm properties. The mechanisms of action of antibiofilm peptides are compared and contrasted with those of antimicrobial peptides. Furthermore, obstacles for the practical translation of candidate peptides into therapeutics and the potential solutions are discussed. Critically, HDPs have the value-added assets of complex functional attributes, particularly antibiofilm and anti-inflammatory activities and their synergy with conventional antibiotics., (© 2021. Springer Nature Limited.)

The very common condition of sinusitis is characterized by persistent inflammation of the nasal cavity, which contributes to chronic rhinosinusitis and morbidity of cystic fibrosis patients. Colonization by opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa triggers inflammation that is exacerbated by defects in the innate immune response. Pathophysiological mechanisms underlying initial colonization of the sinuses are not well established. Despite their extensive use, current murine models of acute bacterial rhinosinusitis have not improved the understanding of early disease stages due to analytical limitations. In this study, a model is described that is technically simple, allows non-invasive tracking of bacterial infection, and screening of host-responses to infection and therapies. The model was modified to investigate longer-term infection and disease progression by using a less virulent, epidemic P. aeruginosa cystic fibrosis clinical isolate LESB65. Tracking of luminescent bacteria was possible after intranasal infections, which were sustained for up to 120 h post-infection, without compromising the overall welfare of the host. Production of reactive oxidative species was associated with neutrophil localization to the site of infection in this model. Further, host-defense peptides administered by Respimat ® inhaler or intranasal instillation reduced bacterial burden and impacted disease progression as well as cytokine responses associated with rhinosinusitis. Thus, future studies using this model will improve our understanding of rhinosinusitis etiology and early stage pathogenesis, and can be used to screen for the efficacy of emerging therapies pre-clinically., Competing Interests: The peptides in this study were invented by RH and co-inventors, assigned to his employer, the University of British Columbia, filed for patent protection, and licensed to ABT Innovations Ltd. in which RH has an ownership position. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alford, Choi, Trimble, Masoudi, Kalsi, Pletzer and Hancock.)

Due to the increasing inability of antibiotics to treat multidrug-resistant (MDR) bacteria, metal and metal oxide nanoparticles have been gaining interest as antimicrobial agents. Among those, silver nanoparticles have been used extensively as broad-spectrum antimicrobial agents. Here, we describe a newly-developed, 10-min (120 °C at 5 bar pressure) microwave-assisted synthesis of silver nanoparticles made from the wood biopolymer lignin as a reducing and capping agent. The resulting lignin-capped silver nanoparticles (AgLNPs) had an average particle diameter of 13.4 ± 2.8 nm. Antimicrobial susceptibility assays against a variety of MDR clinical Gram-positive and Gram-negative pathogens revealed a minimal inhibitory concentration (MIC) of AgLNPs ≤5 µg/mL. AgLNPs (10 µg/mL) showed ≤20% cytotoxicity towards monocytic THP-1 cells and were well tolerated when administered subcutaneously in mice at high concentrations (5 mg at a concentration of 100 mg/mL) with no obvious toxicity. AgLNPs showed efficacy in an in vivo infection (abscess) mouse model against MDR Pseudomonas aeruginosa LESB58 and methicillin-resistant Staphylococcus aureus USA300. A significant decrease in abscess sizes was observed for both strains as well as a reduction in bacterial loads of P. aeruginosa after three days. This demonstrates that microwave-assisted synthesis provides an optimized strategy for the production of AgLNPs while maintaining antimicrobial activity in vitro and in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Therapeutic options to treat multidrug resistant bacteria, especially when present in biofilms, are limited due to their high levels of antibiotic resistance. Here, we report the anti-biofilm and immunomodulatory activities of the host defense peptide (HDP)-mimicking β-peptide polymer (20:80 Bu:DM) and investigated its activity in vivo . The polymer outperformed antibiotics in the removal and reduction of the viability of established biofilms, achieving a maximum activity of around 80% reduction in viability. Interestingly the polymer also exhibited HDP-like immunomodulation in inducing chemokines and anti-inflammatory cytokines and suppressing lipopolysaccharide-induced proinflammatory cytokines. When tested in a murine, high-density skin infection model using P. aeruginosa LESB58, the polymer was effective in diminishing abscess size and reducing bacterial load. This study demonstrates the dual functionality of HDP-mimicking β-peptide polymers in inhibiting biofilms and modulating innate immunity, as well as reducing tissue dermonecrosis.