Design of a Human Defensin 5-Derived Linear Peptide with Potent Antibacterial Efficacy Against Carbapenem-Resistant Acinetobacter baumannii
- 1State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury of PLA, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
- 2College of Basic Medicine, Army Medical University, Chongqing 400038, China
Abstract
The increasing incidence of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) poses a serious threat to global public health, yet treatment options remain scarce. Human defensins (HDs) represent a promising alternative to conventional antibiotics for combating superbugs; however, their structural complexity often hinders synthetic accessibility. Here, we report the rational design of HD5lp5, a linear peptide derived from HD5 through the removal of disulfide bonds and the introduction of arginine residues. This derivative exhibits potent bactericidal activity against CRAB and retains bioactivity in complex physiological environments. Mechanistically, HD5lp5 binds to bacterial lipid A with a dissociation constant of 1.81 nM and destroys membrane integrity in a dose-dependent manner, inducing the leakage of intracellular contents. Beyond membrane disruption, its structural flexibility enables translocation into bacteria. In vitro translation assay reveals that HD5lp5 inhibits ribosomal translation with a half-maximal inhibitory concentration of 0.38 μM. Notably, HD5lp5 exhibits no apparent toxicity in vivo, and it effectively eliminates CRAB colonisation in murine models of intra-abdominal sepsis and irradiation-assisted pulmonary infection, thereby increasing survival rates. Our findings establish HD5lp5 as a promising preclinical candidate for treating life-threatening CRAB.
Related
- CIT8, a machine learning-optimized antimicrobial peptide, exhibits potent activity against carbapenem-resistant Acinetobacter baumannii
- A novel CXCL8(3-72) K11R/G31P-BPI₂₃₃ hybrid protein modulates neutrophil-driven inflammation and protects against carbapenem-resistant Acinetobacter baumannii infection.
- Carbapenem-resistant Acinetobacter baumannii infections in intensive care units: incidence, infection prevention and control, and antimicrobial stewardship practices in the cross-border region between Italy and France, 2019–2022
- Interpreting Graph Neural Networks for Antibacterial Drug Repurposing against Acinetobacter baumannii
- A Toxicity-Reduced NA-CATH-Derived Antimicrobial Peptide Active against Multidrug-Resistant Klebsiella pneumoniae and Acinetobacter baumannii
BibTeX
@article{zhao2026design,
title = {{Design of a Human Defensin 5-Derived Linear Peptide with Potent Antibacterial Efficacy Against Carbapenem-Resistant Acinetobacter baumannii}},
author = {Gaomei Zhao and Chengzhang Tan and Xin Li and Chenwenya Li and Mingrui Shu and Chao Wang and Kainuo Quan and Yongwu He and Jining Gao and Songling Han and Junping Wang and Cheng Wang},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31213885},
url = {https://www.mdpi.com/1420-3049/31/21/3885},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design of a Human Defensin 5-Derived Linear Peptide with Potent Antibacterial Efficacy Against Carbapenem-Resistant Acinetobacter baumannii
AU - Gaomei Zhao
AU - Chengzhang Tan
AU - Xin Li
AU - Chenwenya Li
AU - Mingrui Shu
AU - Chao Wang
AU - Kainuo Quan
AU - Yongwu He
AU - Jining Gao
AU - Songling Han
AU - Junping Wang
AU - Cheng Wang
PY - 2026
DA - 2026/10/28
JO - Molecules
DO - 10.3390/molecules31213885
UR - https://www.mdpi.com/1420-3049/31/21/3885
AB - The increasing incidence of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) poses a serious threat to global public health, yet treatment options remain scarce. Human defensins (HDs) represent a promising alternative to conventional antibiotics for combating superbugs; however, their structural complexity often hinders synthetic accessibility. Here, we report the rational design of HD5lp5, a linear peptide derived from HD5 through the removal of disulfide bonds and the introduction of arginine residues. This derivative exhibits potent bactericidal activity against CRAB and retains bioactivity in complex physiological environments. Mechanistically, HD5lp5 binds to bacterial lipid A with a dissociation constant of 1.81 nM and destroys membrane integrity in a dose-dependent manner, inducing the leakage of intracellular contents. Beyond membrane disruption, its structural flexibility enables translocation into bacteria. In vitro translation assay reveals that HD5lp5 inhibits ribosomal translation with a half-maximal inhibitory concentration of 0.38 μM. Notably, HD5lp5 exhibits no apparent toxicity in vivo, and it effectively eliminates CRAB colonisation in murine models of intra-abdominal sepsis and irradiation-assisted pulmonary infection, thereby increasing survival rates. Our findings establish HD5lp5 as a promising preclinical candidate for treating life-threatening CRAB.
SN - 1420-3049
ER -