Complicated skin and soft tissue infections (cSSTI) are often associated to bacterial biofilms that are hard to eliminate and therefore leads to tissue destruction and consequent delay or impairment of healing. The current standard-of-care for these infections is extensive and involves antibiotic therapy. The most severe cases culminate in impatient hospital admission, where infections can be exacerbated by hospital acquired pathogens for which few efficient antibiotics are available (doi: 10.2147/IDR.S172366). New options for management and treatment of cSSTI are urgently needed, and the current biomedical approaches aim at providing protection against multidrug-resistant (MDR) bacteria to the open wound together with a matrix scaffold, often collagen-based, to boost reestablishment of a healthy skin through a fast-healing process (doi: 10.2147/DMSO.S36024). We have thus designed hybrid peptides encompassing an antimicrobial sequence and a collagen-boosting sequence covalently linked to each other, aiming at a final dual-action peptide construct with antimicrobial and wound-healing properties. The most promising peptide, 3.1-PP4: i) displays potent antimicrobial activity against Gram-positive and Gram-negative bacteria; ii) is equally potent against gram-negative MDR clinical isolates; iii) hampers the formation of, or disaggregates, biofilms of MDR clinical isolates of K. pneumoniae, and iv) retains the collagenesis-inducing behavior of the collagen-boosting parent peptide (doi: 10.3389/fmicb.2019.01915). We next performed chemical modification of peptide 3.1-PP4, by conjugation with an imidazole-based ionic liquid via click chemistry. The resulting conjugate, MeIm-3.1-PP4, retained the parent peptide’s antibacterial and antibiofilm activity, while exhibiting much improved stability towards tyrosinase-mediated modification (doi: 10.3390/ijms21176174). In conclusion, both peptides 3.1-PP4 and MeIm-3.1-PP4, are highly promising leads towards development of innovative topical formulations to tackle skin infections.
Acknowledgements: We thank Fundação para a Ciência e Tecnologia for funding through projects UIDB/50006/2020 and POCI-01-0145-FEDER-031781, and for Doctoral Grant PD/BD/135073/2017 (AG).