###### Abstract  
Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibioticfilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (\(N\)-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicids: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of _Pseudomonas aeruginosa_, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory-factory effects which is comparable to that of \"the last resource\" antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies. antimicrobial peptide; peptidomimetic; peptoid; ESKAPE pathogens; multidrug resistance; biofilm +
Footnote †: journal: _pharmacacuticals_
residues and the ability to adopt an amphipathic conformation upon interacting with membranes. They are usually unstructured in aqueous solutions, but their positive net charge drives the initial absorption to bacterial membranes which are rich in negative phospholipids, and their amphipathic structure allows for their insertion into the membrane. CAMPs alter the fluidity, thickness and curvature of the membrane; moreover, they can induce the formation of pores, which are lethal both to actively dividing and resting cells, or even cause the micellization of the membrane. Furthermore, several CAMPs show antibiofilm activity, being able to prevent the adhesion of bacterial cells to surfaces, kill cells inside the biofilm matrix or even induce the disaggregation of the biofilm by interacting with the components of the extracellular matrix [9; 10; 11]. The multi-target mechanism of CAMPs makes the development of bacterial resistance, as has been observed for conventional antibiotics, very difficult and unlikely. In addition to directly killing bacteria, several CAMPs also display immunomodulatory functions, including the ability to inhibit the endotoxin-induced production of proinflammatory cytokines [12]. In most cases, this modulatory activity is due to direct binding to endotoxins like lipopolysaccharidesaccharides (LPSs), and lipoteichoic acid (LTA) [13; 14; 15; 16; 17; 18; 19; 20]. Thus, CAMPs act as scavengers, segregating endotoxins in complexes which cannot bind to their receptors (e.g., the Toll-like receptors TLR-2 and TLR-4). Very intriguingly, the cationic/amphipathic nature of CAMPs seems to also be responsible for their ability to bind to endotoxins and endotoxin receptors [21]. This peculiar combination of properties makes CAMPs very attractive drugs. However, their sensitivity to proteolytic degradation can reduce their half-lives and, most importantly, limits their possible routes of administration.