Boosting Cosmeceutical Peptides: Coupling Imidazolium-Based Ionic Liquids to Pentapeptide-4 Originates New Leads with Antimicrobial and Collagenesis-Inducing Activities

ABSTRACT Following our previous reports on dual-action antibacterial and collagenesis-inducing hybrid peptide constructs based on “pentapeptide-4” (PP4, with amino acid sequence KTTKS), whose N-palmitoyl derivative is the well-known cosmeceutical ingredient Matrixyl, herein we disclose novel ionic liquid/PP4 conjugates (IL-KTTKS). These conjugates present potent activity against either antibiotic-susceptible strains or multidrug resistant clinical isolates of both Gram-positive and Gram-negative bacterial species belonging to the so-called “ESKAPE” group of pathogens. Noteworthy, their antibacterial activity is preserved in simulated wound fluid, which anticipates an effective action in the setting of a real wound bed. Moreover, their collagenesis-inducing effects in vitro are comparable to or stronger than those of Matrixyl. Altogether, IL-KTTKS exert a triple antibacterial, antifungal, and collagenesis-inducing action in vitro. These findings provide solid grounds for us to advance IL-KTTKS conjugates as promising leads for future development of topical treatments for complicated skin and soft tissue infections (cSSTI). Further studies are envisaged to incorporate IL-conjugates into suitable nanoformulations, to reduce toxicity and/or improve resistance to proteolytic degradation. IMPORTANCE As life expectancy increases, diseases causing chronic wound infections become more prevalent. Diabetes, peripheral vascular diseases, and bedridden patients are often associated with non-healing wounds that become infected, resulting in high morbidity and mortality. This is exacerbated by the fact that microbes are becoming increasingly resistant to antibiotics, so efforts must converge toward finding efficient therapeutic alternatives. Recently, our team identified a new type of constructs that combine (i) peptides used in cosmetics to promote collagen formation with (ii) imidazolium-based ionic liquids, which have antimicrobial and skin penetration properties. These constructs have potent wide-spectrum antimicrobial action, including against multidrug-resistant Gram-positive and Gram-negative bacteria, and fungi. Moreover, they can boost collagen formation. Hence, this is an unprecedented class of lead molecules toward development of a new topical medicine for chronically infected wounds.