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.
Highlights
The development of antibiotic drugs has greatly reduced the incidence and mortality of bacterial infections [1]
The synthetic Feleucin-K3 analogs were mainly modified by α-(4-pentenyl)-Ala to improve the antimicrobial activity, stability and decrease the hemolytic activity
The masses of the peptides were characterized by electrospray ionization mass spectrometry (ESI-MS) and were shown in reflected the hydrophobicity, and the TR values were listed from long to short in the following order: K63 > K71 > K69 > K68 > K67 > K70 > K64
Summary
The development of antibiotic drugs has greatly reduced the incidence and mortality of bacterial infections [1]. The overreliance on antibiotics has aggravated the antimicrobial resistance (AMR), thereby seriously threatening global public health [2]. Antimicrobial peptides (AMPs) have broad-spectrum antimicrobial activity due to their rapid bactericidal ability and mechanism of action, which is mainly through nonspecific membrane destruction, attracting widespread attention as promising new antibiotic candidates [3]. The formation of biofilms has always been considered one of the main reasons by which bacteria develop resistance, making it more difficult for conventional antibiotics to treat bacterial infections [4]. There are reports that AMPs can inhibit and eradicate biofilms to treat biofilm-related infections [5]. Some disadvantages of AMPs, such as high toxicity and poor proteolytic stability, limit their clinical applications [6]
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