Identification of New Nitric Oxide-Donating Peptides with Dual Biofilm Eradication and Antibacterial Activities for Intervention of Device-Related Infections

Abstract

Implantable medical device-related infections with biofilms have become a significant challenge in clinics. Based on the potential bacteria biofilm dispersing effect of nitric oxide (NO) and the unique antibacterial activity of antimicrobial peptides (AMP), we synthesized five peptides and selected the most potent one to conjugate its N-terminal with a furoxan moiety to offer a hitherto unknown NO-donating antimicrobial peptide (FOTyr-AMP), which exhibited Staphylococcus aureus and Escherichia coli biofilm dispersion and eradication, and potent antibacterial activities in vitro. In an implanted biofilm infection mice model, topical subcutaneous injection of FOTyr-AMP allowed synergetic eradication of bacterial biofilms and potent antibacterial activity, superior to the antibiotic cephalosporin C. Given the low hemolysis effect, little influence on the blood pressure, and potent in vivo efficacy of FOTyr-AMP, it is clear that subcutaneous administration of FOTyr-AMP could be a promising approach for the intervention of medical device-related biofilm infections with desirable safety.

Photoactivatable Nitric Oxide-Releasing Gold Nanocages for Enhanced Hyperthermia Treatment of Biofilm-Associated Infections

“…Biofilm biomass was determined through the crystal violet assay as reported by Wang et al, and the detailed procedure is presented in the SI. 21 Live/Dead Staining Assay. To further evaluate the antibacterial and biofilm dispersal properties, the Live/Dead staining assay was employed, and confocal microscopy (Nikon C2) was utilized for observation.…”

“…The detailed protocol was carried out according to the previously reported method and is provided in the SI. 21,59 Bacteria and Biofilm Morphology Observation. The morphologies of bacteria and biofilms after treatment were characterized using a modified method reported by Luo et al 60 The detailed procedure is presented in the SI.…”

Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications

“…Examples of commonly used NO-donors, hybrid and macromolecular NO-releasing designs [21][22][23][24][25][26]NO at various concentrations can exert antimicrobial effects and/or potentiate the activity of antimicrobials Similar to mammalian systems, the activity of NO on bacteria and bacterial biofilms is dependent on its local concentration. In bacteria, NO may be generated from L-arginine by bacterial NOS [27][28][29].…”

“…Beyond C3Ds, antimicrobial peptides have also been conjugated to a NO-donating furoxan moiety. The hybrid compound displayed synergistic activity against S. aureus and E. coli in inhibition of biofilm growth, biofilm dispersal, and eradication of both biofilm and planktonic cells compared to the AMPs or furoxan donors alone, with low hemolysis and effects on blood pressure when administered subcutaneously in mice models [26].…”

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

“…For example, 3-cyano- and 3-nitro-4-phenylfuroxans revealed promising antiplatelet activity [ 111 ], while the latter compound also inhibited Pseudomonas aeruginosa PAO1 growth and prevented PAO1 biofilm formation [ 112 ]. Several furoxan–peptide hybrids also demonstrated antimicrobial activity against Staphylococcus aureus and Escherichia coli biofilm formation [ 113 ]. A highly potent drug candidate PRG150 (3-methylfuroxan-4-carbaldehyde) is considered as a novel analgesic for the effective treatment of painful diabetic neuropathy.…”