A promising antibiotic candidate, brevinin-1 analogue 5R, against drug-resistant bacteria, with insights into its membrane-targeting mechanism

Wanchen Zou, Ruize Sun, Aifang Yao, Mei Zhou, Xiaoling Chen, Chengbang Ma, Tao Wang, Yangyang Jiang, Tianbao Chen, Chris Shaw, Lei Wang

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
71 Downloads (Pure)

Abstract

In recent decades, antimicrobial peptides (AMPs) have held great promise as novel antibiotic agents. However, they have generally been excluded from clinical use due to certain limitations, such as poor biocompatibility and sensitivity to environmental conditions. In this study, we report a novel brevinin-1 type antimicrobial peptide B1LTe, derived from the skin secretion of . Although the novel peptide B1LTe exhibited remarkable antimicrobial effects, its narrow therapeutic index (TI) can result in adverse drug reactions. Thus, the rational design by systematically scanning and replacing the inherent hydrophobic and cationic residues (Leucine and Lysine) with their D-enantiomeric counterparts was conducted to enhance the application potential of B1LTe. Simultaneously, we also applied lysine-to-arginine substitution within the modification. Among the derivates, 5 R demonstrated the highest selectivity and effectiveness against Methicillin-resistant (MRSA), clinic-isolated ( ) strain, ranging from their planktonic to biofilm cells, both in vitro and in vivo. Furthermore, the remarkable adaptation of 5 R in saline and 20% serum indicates its potential for clinical application. We employed the in silico approach, which revealed the mechanism of interaction between 5 R and bacterial membranes. In addition, further mechanistic studies of 5 R elucidated the association between the collapsed proton motive force (PMF) and membrane perturbation as peptides aggregate on the bacterial membrane. Overall, our study suggests the D-enantiomeric 5 R can be a promising antibiotic agent against MDR bacteria in further clinical development and highlights the significance of cellular PMF as a potential target for the research of peptides' mode of action
Original languageEnglish
Pages (from-to)5719-5737
Number of pages19
JournalComputational and Structural Biotechnology Journal
Volume21
DOIs
Publication statusPublished - 23 Nov 2023

Keywords

  • D-amino acids
  • Antibacterial mechanism
  • Drug resistance
  • Biofilm
  • Antimicrobial peptide

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