A Toxicity-Reduced NA-CATH-Derived Antimicrobial Peptide Active against Multidrug-Resistant Klebsiella pneumoniae and Acinetobacter baumannii
5 affiliations
- 1Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences , , ,
- 2Chinese Academy of Medical Sciences & Peking Union Medical College , , ,
- 3Beijing Sport University , , ,
- 4University of Chinese Academy of Sciences , ,
- 5Institute of Microbiology, Chinese Academy of Sciences , , ,
Abstract
Multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii pose major public health threats, while biofilm formation further reduces the effectiveness of existing antibiotics. Although antimicrobial peptides are considered potential alternatives, their development is frequently limited by systemic toxicity. In this study, five antimicrobial peptides were evaluated against clinical isolates of K. pneumoniae and A. baumannii for antimicrobial activity, inhibition of biofilm biomass, and hemolytic activity, and NA-CATH was selected for subsequent optimization because of its comparatively strong in vitro activity and low hemolysis. Structure-guided rational design and computational screening of nearly 50,000 variants were then applied to improve its activity–toxicity profile. Despite its favorable in vitro performance, NA-CATH caused 100% mortality in Galleria mellonella, indicating substantial in vivo toxicity. Initial rational modifications reduced toxicity but were accompanied by decreased antimicrobial activity. Subsequent computational screening identified NA-7, which retained antimicrobial activity, increased survival in K. pneumoniae-infected larvae compared with the parental peptide, and showed lower acute toxicity and fewer renal histopathological alterations in mice. Collectively, NA-7 exhibited an improved balance between antimicrobial activity and in vivo tolerability relative to NA-CATH in the evaluated models, supporting its further investigation as an optimized lead peptide and demonstrating the utility of iterative computational screening for antimicrobial peptide optimization.
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BibTeX
@article{zuo2026toxicityreduced,
title = {{A Toxicity-Reduced NA-CATH-Derived Antimicrobial Peptide Active against Multidrug-Resistant Klebsiella pneumoniae and Acinetobacter baumannii}},
author = {Jing Zuo and Jialin Li and Yibo Zhang and Yanbin Chang and Yi Li and Xiujun Liu and Songnian Hu and Li Li and Junping Li and Yingfeng Luo and Liping Bai},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c06889},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c06889/5456994/A-Toxicity-Reduced-NA-CATH-Derived-Antimicrobial},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A Toxicity-Reduced NA-CATH-Derived Antimicrobial Peptide Active against Multidrug-Resistant Klebsiella pneumoniae and Acinetobacter baumannii
AU - Jing Zuo
AU - Jialin Li
AU - Yibo Zhang
AU - Yanbin Chang
AU - Yi Li
AU - Xiujun Liu
AU - Songnian Hu
AU - Li Li
AU - Junping Li
AU - Yingfeng Luo
AU - Liping Bai
PY - 2026
DA - 2026/10/23
JO - ACS Omega
DO - 10.1021/acsomega.6c06889
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c06889/5456994/A-Toxicity-Reduced-NA-CATH-Derived-Antimicrobial
AB - Multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii pose major public health threats, while biofilm formation further reduces the effectiveness of existing antibiotics. Although antimicrobial peptides are considered potential alternatives, their development is frequently limited by systemic toxicity. In this study, five antimicrobial peptides were evaluated against clinical isolates of K. pneumoniae and A. baumannii for antimicrobial activity, inhibition of biofilm biomass, and hemolytic activity, and NA-CATH was selected for subsequent optimization because of its comparatively strong in vitro activity and low hemolysis. Structure-guided rational design and computational screening of nearly 50,000 variants were then applied to improve its activity–toxicity profile. Despite its favorable in vitro performance, NA-CATH caused 100% mortality in Galleria mellonella, indicating substantial in vivo toxicity. Initial rational modifications reduced toxicity but were accompanied by decreased antimicrobial activity. Subsequent computational screening identified NA-7, which retained antimicrobial activity, increased survival in K. pneumoniae-infected larvae compared with the parental peptide, and showed lower acute toxicity and fewer renal histopathological alterations in mice. Collectively, NA-7 exhibited an improved balance between antimicrobial activity and in vivo tolerability relative to NA-CATH in the evaluated models, supporting its further investigation as an optimized lead peptide and demonstrating the utility of iterative computational screening for antimicrobial peptide optimization.
SN - 2470-1343
ER -