In Vitro ADME Properties of Two Novel Antimicrobial Peptoid-Based Compounds as Potential Agents against Canine Pyoderma.

Ines Greco,Jeffrey Watts,Jason Koch,Peter Damborg,Jaspreet Vasir,Paul Hansen,Bernard Hummel,Johannes Hansen,Hanne Nielsen

doi:10.3390/molecules23030630

Ines Greco, Jeffrey Watts + Show 7 more

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https://doi.org/10.3390/molecules23030630

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Abstract

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid-based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides.

Highlights

The emergence of bacterial pathogens resistant to multiple antimicrobial agents over the past decades is a growing public health threat, and there is an urgent need for novel antimicrobial drugs for human and veterinary use [1,2]
Molecules 2018, 23, 630 untreatable with antimicrobial agents licensed for systemic use in dogs
S. pseudintermedius and host toxicity vitrotoxicity measured as lytic activity as against activity against red blood cells

Summary

Introduction

The emergence of bacterial pathogens resistant to multiple antimicrobial agents over the past decades is a growing public health threat, and there is an urgent need for novel antimicrobial drugs for human and veterinary use [1,2]. Canine skin infections constitute the main cause of antibiotic use [3]. Staphylococcus pseudintermedius is the primary pathogen of this disease, as it is isolated from around 90% of canine clinical skin samples [4]. The worldwide emergence of methicillin-resistant S. pseudintermedius (MRSP) [5] has resulted in infections untreatable with antimicrobial agents licensed for systemic use in dogs. Molecules 2018, 23, 630 untreatable with antimicrobial agents licensed for systemic use in dogs. There is an urgent need to alternative develop alternative antimicrobial agentsthis to pathogen

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