Novel Feleucin-K3-Derived Peptides Modified with Sulfono-γ-AA Building Blocks Targeting Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infections

Abstract

The prevalence of multidrug-resistant bacterial infections has led to dramatically increased morbidity and mortality. Antimicrobial peptides (AMPs) have great potential as new therapeutic agents to reverse this dangerous trend. Herein, a series of novel AMP Feleucin-K3 analogues modified with unnatural peptidomimetic sulfono-γ-AA building blocks were designed and synthesized. The structure–activity, structure–toxicity, and structure–stability relationships were investigated to discover the optimal antimicrobial candidates. Among them, K122 exhibited potent and broad-spectrum antimicrobial activity and high selectivity. K122 had a rapid bactericidal effect and a low tendency to induce resistance. Surprisingly, K122 showed excellent effectiveness against bacterial pneumonia. For biofilm and local skin infections, K122 significantly decreased the bacterial load and improved tissue injury at a dose of only 0.25 mg/kg, which was 160 times lower than the concentration deemed to be safe for local dermal applications. In summary, K122 is an outstanding candidate for the treatment of multidrug-resistant bacteria and biofilm infections.

To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide

“…Membrane disruptive antimicrobial peptides (AMPs), which occur naturally as part of the innate immune system, offer an opportunity to address multidrug-resistant (MDR) bacteria because of their unspecific mechanism of action, against which resistance does not occur easily. − Such AMPs are however unstable in serum and most often toxic owing to their membrane disruptive amphiphilic and usually α-helical structure triggering their antibacterial effect. Their properties can be improved by sequence optimization, − whereby the most versatile approach consists in introducing non-natural structural elements such as d -amino acids, − non-natural residues, β- or γ-amino acids, , isopeptide bonds, or entirely non-peptidic elements such as spermine or fatty acids. , A complete redesign of AMPs is also possible in the form of dimers, cyclic or bicyclic staples, − small molecules, peptoids, , foldamers, or dendrimers. , …”

“… 1 − 3 Such AMPs are however unstable in serum and most often toxic owing to their membrane disruptive amphiphilic and usually α-helical structure triggering their antibacterial effect. Their properties can be improved by sequence optimization, 4 − 7 whereby the most versatile approach consists in introducing non-natural structural elements 8 such as d -amino acids, 9 − 13 non-natural residues, 14 β- or γ-amino acids, 15 , 16 isopeptide bonds, 17 or entirely non-peptidic elements such as spermine 18 or fatty acids. 19 , 20 A complete redesign of AMPs is also possible in the form of dimers, 21 cyclic or bicyclic staples, 22 − 24 small molecules, 25 peptoids, 26 , 27 foldamers, 28 or dendrimers.…”

Michael Addition Reaction between Dehydroalanines and Phosphites Enabled the Introduction of Phosphonates into Oligopeptides

“…In line with our recent late-stage peptide modification efforts, − including those based on Dha, − and antimicrobial peptide development, − we sought to develop a rapid and facile method for peptide phosphorylation using the P Michael addition of readily available phosphites to the Dha residue, which would be a novel strategy for the screening of potential antimicrobial phosphopeptide hits (Scheme B).…”

“…Considering the unique advantages and latent capacity of phosphorylation modification in the discovery of pharmaceutically active peptides − and on the basis of our recent research interest in antimicrobial peptide drug discovery, − a class of ultrashort antimicrobial active peptides were chosen as the target molecules, , to explore novel antimicrobial peptide hits by phosphorylation modification (Scheme ). It was observed that the chemically modified peptides exhibited a notable improvement in antibacterial activity against Gram-negative bacteria.…”