Authors
Jin Kyeong Lee, Chae Yeong Lee, Minwon Son, Byeongkwon Kim, Junho Jeong, Yeongjoon Lee, Woo Cheol Lee, Eunha Hwang, Eunhee Kim, Myeong Seon Jeong, Yangmee Kim
Published in
Journal of medicinal chemistry. Sep 04, 2025. Epub Sep 04, 2025.
Abstract
We explored the lipopolysaccharide-binding properties of adenylate kinase from Mycobacterium tuberculosis (MtAdk) to facilitate the design of novel peptide antibiotics. Notably, we de novo designed 11-mer peptides derived from the AMP-binding domain (Lys44 to Asp54) of MtAdk. Among 71 designed peptides, DD-S067 was the most effective, especially against carbapenem-resistant Acinetobacter baumannii (CRAB), with minimal development of drug resistance. DD-S067 exhibited multiple antibacterial mechanisms, including disrupting both the outer and inner bacterial membranes, and inducing reactive oxygen species that trigger lipid peroxidation. Transcriptome analysis revealed that DD-S067 disrupted key cellular pathways in CRAB by inhibiting the electron transport chain and triggering oxidative stress responses, ultimately suppressing CRAB virulence mechanisms. Furthermore, DD-S067 exhibited significant protective effects in a CRAB-induced septic shock mouse model, highlighting its potential as a novel peptide antibiotic for treating Gram-negative infections. These findings pave the way for innovative strategies in developing protein-based antibiotics.
PMID:
40906914
Bibliographic data and abstract were imported from PubMed on 05 Sep 2025.
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