Abstract
The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. In conclusion, our data support the development of defensin-derived antimicrobial agents as a novel approach to fight multidrug-resistant bacteria, where Pam-3 appears as a particularly promising microbiota-preserving candidate.
Highlights
The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections
Lipopeptides are used as antibiotics which are highly active against multidrug-resistant bacteria and fungi[24,25]
Pam-1 to Pam-5, based on the recently discovered octapeptide (Fig. 1a). This set of peptides was screened for their antimicrobial activity against several pathogenic bacteria using a radial diffusion assay (Fig. 1b)
Summary
The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. Antimicrobial peptides (AMPs) are small, cationic peptides existing in all multicellular organisms and exhibit a broad range of antimicrobial and immunological properties[9] They are considered a promising treatment option and have the potential to be a new generation of antimicrobials against multidrug-resistant bacteria. De Breij et al demonstrated the potential of novel antimicrobial peptides by developing SAAP-148, which showed promising effects against biofilm-associated skin infections in ex vivo human skin and murine skin in vivo[10]. The most prominent class of AMPs in humans, are key effector molecules of innate immunity These peptides protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces[12,13,14,15]. We have recently shown that this creates an eight-amino acid carboxyl-terminal fragment (called octapeptide) with retained antimicrobial activity, albeit low in vivo stabilty[21]
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