Citation: Mingming Xu, Binglei Li, Junfei Zhou, Xudong Hang, Chuanlin Jin, Chujie Lu, Wei Lin, Xinyi Wei, Er-Xin Shang, Liping Zeng, Monday M. Onakpa, Oluwatosin O. Johnson, Chun-Tao Che, Jin-Ao Duan, Hongkai Bi, Ming Zhao. Unprecedented ent-kaurane heterodimers from Icacina oliviformis: Potent anti-Helicobacter pylori leads targeting enoyl-ACP reductase FabI[J]. Chinese Chemical Letters, ;2026, 37(11): 112289. doi: 10.1016/j.cclet.2025.112289 shu

Unprecedented ent-kaurane heterodimers from Icacina oliviformis: Potent anti-Helicobacter pylori leads targeting enoyl-ACP reductase FabI

Mingming Xu ^{a, 1} ,
Binglei Li ^{b, c, 1} ,
Junfei Zhou ^{a, 1} ,
Xudong Hang ^{b, c, 1} ,
Chuanlin Jin ^a ,
Chujie Lu ^{a, d} ,
Wei Lin ^d ,
Xinyi Wei ^a ,
Er-Xin Shang ^a ,
Liping Zeng ^c ,
Monday M. Onakpa ^e ,
Oluwatosin O. Johnson ^f ,
Chun-Tao Che ^g ,
Jin-Ao Duan ^{a, *,} ,
Hongkai Bi ^{b, c, *,} ,
Ming Zhao ^{a, g, *,}

a.
Jiangsu Provincial Key Laboratory of Functional Substances in Traditional Chinese Medicine Formulae and Innovative Drug Discovery, Jiangsu Collaborative Innovation Centre of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Centre of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
b.
NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine, Hainan Medical University, Haikou 571199, China
c.
Department of Pathogen Biology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing 211166, China
d.
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
e.
Department of Veterinary Pharmacology and Toxicology, University of Abuja, Abuja 920001, Nigeria
f.
Deparment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, CMUL Campus, Lagos 100254, Nigeria
g.
Department of Pharmaceutical Science, Retzky College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States

dja@njucm.edu.cn

hkbi@muhn.edu.cn

mingzhao@njucm.edu.cn

Received Date: 17 September 2025
Revised Date: 12 December 2025
Accepted Date: 15 December 2025
Available Online: 17 December 2025

Figures(3)

The escalating global prevalence of antibiotic-resistant Helicobacter pylori infections necessitates the development of novel therapeutics targeting specific bacterial pathways. From Icacina oliviformis leaves, we isolated twelve novel diterpenoids (1–12), including two unprecedented dimeric scaffolds, alongside four known analogs (13–16). Structural elucidation via nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), electronic circular dichroism (ECD), DP4+ analysis, and X-ray crystallography revealed three groundbreaking architectures: 1–3 (oliviformisones A–C) as the first ent-kaurane-(8,14-seco-ent-kaurane) spiro-heterodimers featuring a unique 6/6/6/5/6/7/6/6-fused octocyclic core with a 2-oxatricyclo[6.2.1.0^3,8]hendecane spiro linker; 4–6 (oliviformisones D–F) as pioneering ent-kaurane-(ent-abietane) dimers via an unprecedented C-17–C-17′ linkage; 7 and 8 as the first ent-kaurane-(8,14-seco-ent-kaurane) dimers bridged by a 1,3-dioxane moiety. Proposed biosynthetic pathways for 1, 2, 4, and 5 involve key retro-aldol and nucleophilic reactions. Notably, 1 and 3 exhibited potent anti-H. pylori activity (minimum inhibitory concentration (MIC) = 2–16 μg/mL), with 3 showing additive effects with amoxicillin (fractional inhibitory concentration index (FICI) = 0.625). Mechanistic studies confirmed 1 as a high-affinity fatty acid biosynthesis enoyl-acyl carrier protein reductase Ⅰ (FabI) inhibitor (K_d = 6.34 nmol/L), competitively blocking enoyl-acyl carrier protein (ACP) reductase (K_i = 8.9 μmol/L) to down-regulate bacterial fatty acid biosynthesis. Comparative enzymatic and docking analyses further revealed that 1 selectively inhibits H. pylori FabI over human and commensal homologs, while showing low cytotoxicity toward normal gastric epithelial cells. This work identifies 1 as the first natural product-derived selective FabI inhibitor with anti-H. pylori activity, validates FabI as a target for species-selective therapy, and unveils ent-kaurane diterpenoids as a structurally diverse pharmacophore for antibacterial development.
- Icacina oliviformis,
- ent-Kaurane heterodimers,
- Anti-Helicobacter pylori activity,
- Additive effects,
- Enoyl-ACP reductase FabI
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