Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria

Abstract

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it was found that the fourth residue of Feleucin-K3 is important for antimicrobial activity. After α-(4-pentenyl)-Ala was introduced into this position, both the antimicrobial activity and stability were greatly improved. Herein, to improve the limitations of Feleucin-K3, this unnatural amino acid was further introduced into different positions of Feleucin-K3. Among these synthetic Feleucin-K3 analogs, the N-terminal-substituted analog Feleucin-K65 (K65) and C-terminal-substituted analog Feleucin-K70 (K70) had preferable antimicrobial activity. In particular, their antimicrobial activities against multidrug-resistant bacteria were more potent than that of antibiotics. The stabilities of these peptides in salt and serum environments were improved compared with those of Feleucin-K3. In addition, these analogs had low hemolytic activity and AMR. More importantly, they effectively inhibited biofilm formation and exhibited considerable efficacy compared with traditional antibiotics against biofilm infection caused by methicillin-resistant Staphylococcus aureus (MRSA). In antimicrobial mechanism studies, K65 and K70 mainly permeated the outer membrane and depolarized the cytoplasmic membrane, resulting in cellular component leakage and cell death. In summary, analogs K65 and K70 are potential antimicrobial alternatives to solve the antibiotic crisis.

A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis

“…It is likely that d -amino acids cannot be recognized by proteases in mammals and that alanine replacement changed the steric hindrance and improved the hydrophobicity of the peptide 33 , 34 , 36 , 37 , 38 , 39 , 40 . Studies have shown that the introduction of α -(4-pentenyl)-Ala into peptide Feleucin-K3 improved its antimicrobial activity and stability 41 , 42 . Based on the aforementioned findings, unnatural hydrophobic alanine ( α -(4-pentenyl)-Ala and d -Ala) was selected to replace residues Asn3 and Asn4 of DR8.…”

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

“…MIC determination method was as previously described . During the 20 d of induction, the sub-MIC concentration of bacteria suspension was cultured to measure the MIC repeatedly.…”

“…MIC determination method was as previously described. 12 During the 20 d of induction, the sub-MIC concentration of bacteria suspension was cultured to measure the MIC repeatedly. The development of bacterial resistance was defined as a more than fourfold increase in MICs compared to the initial MICs.…”

“…11 Our previous studies revealed that the positively charged amino acids were comparatively conserved in AMP, but minor changes in hydrophobicity considerably impacted activity and toxicity. 12,13 Therefore, the present study focused on introducing sulfono-γ-AA building blocks with different hydrophobic side chains to alter the hydrophobicity of the residues of Feleucin-K3, as such modification should not induce significant conformational change but could potentially enhance the stability and activity (Schemes 1 and 2). 14 The chosen R 1 groups were benzyl or isobutyl, the side chain of Phe or Leu in the parent Feleucin-K3, respectively.…”

Self-fused concatenation of interferon with enhanced bioactivity, pharmacokinetics and antitumor efficacy

“…[1][2][3][4] However, they have conspicuous limitations such as quick renal clearance, poor stability and strong immunogenicity during their use, thus requiring frequent administrations to achieve therapeutic effects, which in turn increases the chance of dramatically oscillating concentrations in blood and adverse effects as well as poor patient compliance. 1,5,6 Many strategies, such as dissolving in appropriate buffers, 7 loading in nanocarriers, [8][9][10] site-specic mutation, 11,12 immobilization in functional materials, 13 modication with polymers, 14,15 etc., can effectively improve the stability and drug delivery. Covalent conjugation of poly(ethylene glycol) (PEG) on the surface of protein therapeutics, named PEGylation, is a type of important strategy to extend the half-life of biomolecules.…”