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Article

An AI-Designed Antibody-Engineered Probiotic Therapy Targeting Urease to Combat Helicobacter pylori Infection in Mice

1
Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
2
Ningxia Key Laboratory of Clinical Pathogenic Microorganisms, School of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China
*
Author to whom correspondence should be addressed.
Microorganisms 2025, 13(9), 2043; https://doi.org/10.3390/microorganisms13092043
Submission received: 16 May 2025 / Revised: 29 July 2025 / Accepted: 30 August 2025 / Published: 1 September 2025
(This article belongs to the Section Medical Microbiology)

Abstract

Helicobacter pylori (Hp), a Class I carcinogen infecting over 50% of the global population, is increasingly resistant to conventional antibiotics. This study presents an AI-engineered probiotic strategy targeting urease, a key Hp virulence factor. A humanized single-domain antibody (UreBAb), previously identified and selected in our laboratory, was synthesized commercially and modeled using AlphaFold2, with structural validation conducted via SAVES 6.0. Molecular docking (PyMOL/ClusPro2) and binding energy analysis (InterProSurf) identified critical urease-active residues: K40, P41, K43, E82, F84, T86, K104, I107, K108, and R109. Machine learning-guided optimization using mCSA-AB, I-Mutant, and FoldX prioritized four mutational hotspots (K43, E82, I107, R109), leading to the generation of nine antibody variants. Among them, the I107W mutant exhibited the highest activity, achieving 65.6% urease inhibition—a 24.95% improvement over the wild-type antibody (p < 0.001). Engineered Escherichia coli Nissle 1917 (EcN) expressing the I107W antibody significantly reduced gastric HP colonization by 4.42 log10 CFU in the treatment group and 3.30 log10 CFU in the prevention group (p < 0.001 and p < 0.05, respectively), while also suppressing pro-inflammatory cytokine levels. Histopathological (H&E) analysis confirmed that the I107W antibody group showed significantly enhanced mucosal repair compared to wild-type probiotic-treated mice. Notably, 16S rRNA sequencing revealed that intestinal microbiota diversity and the abundance of core microbial species remained stable across different ethnic backgrounds. By integrating AI-guided antibody engineering with targeted probiotic delivery, this platform provides a transformative and microbiota-friendly strategy to combat antibiotic-resistant Hp infections.
Keywords: Helicobacter pylori; AI-driven antibody design; Ab single-domain antibodies; Escherichia coli Nissle 1917 engineered probiotics; flora homeostasis Helicobacter pylori; AI-driven antibody design; Ab single-domain antibodies; Escherichia coli Nissle 1917 engineered probiotics; flora homeostasis

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MDPI and ACS Style

Zhong, F.; Liu, X.; Wang, X.; Hou, M.; Guo, L.; Luo, X. An AI-Designed Antibody-Engineered Probiotic Therapy Targeting Urease to Combat Helicobacter pylori Infection in Mice. Microorganisms 2025, 13, 2043. https://doi.org/10.3390/microorganisms13092043

AMA Style

Zhong F, Liu X, Wang X, Hou M, Guo L, Luo X. An AI-Designed Antibody-Engineered Probiotic Therapy Targeting Urease to Combat Helicobacter pylori Infection in Mice. Microorganisms. 2025; 13(9):2043. https://doi.org/10.3390/microorganisms13092043

Chicago/Turabian Style

Zhong, Feiliang, Xintong Liu, Xuefang Wang, Mengyu Hou, Le Guo, and Xuegang Luo. 2025. "An AI-Designed Antibody-Engineered Probiotic Therapy Targeting Urease to Combat Helicobacter pylori Infection in Mice" Microorganisms 13, no. 9: 2043. https://doi.org/10.3390/microorganisms13092043

APA Style

Zhong, F., Liu, X., Wang, X., Hou, M., Guo, L., & Luo, X. (2025). An AI-Designed Antibody-Engineered Probiotic Therapy Targeting Urease to Combat Helicobacter pylori Infection in Mice. Microorganisms, 13(9), 2043. https://doi.org/10.3390/microorganisms13092043

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