Single Deletion Unmasks Hidden Anti-Gram-Negative Bacterial Activity of an Insect Defensin-Derived Peptide.
J Med Chem
; 67(4): 2512-2528, 2024 Feb 22.
Article
em En
| MEDLINE
| ID: mdl-38335999
ABSTRACT
Insect defensins are a large family of antimicrobial peptides primarily active against Gram-positive bacteria. Here, we explore their hidden anti-Gram-negative bacterial potential via a nature-guided strategy inspired by natural deletion variants of Drosophila defensins. Referring to these variants, we deleted the equivalent region of an insect defensin with the first cysteine-containing N-terminus, and the last three cysteine-containing C-terminal regions remained. This 15-mer peptide exhibits low solubility and specifically targets Gram-positive bacteria. Further deletion of alanine-9 remarkably improves its solubility, unmasks its hidden anti-Gram-negative bacterial activity, and alters its states in different environments. Intriguingly, compared with the oxidized form, the 14-mer reduced peptide shows increased activity on Gram-positive and Gram-negative bacteria through a membrane-disruptive mechanism. The broad-spectrum activity and tolerance to high-salt environments and human serum, together with no toxicity to mammalian or human cells, make it a promising candidate for the design of new peptide antibiotics against Gram-negative bacterial infections.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cisteína
/
Antibacterianos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article