2. Academic Validation
  3. SU3327: A multi-target compound targeting bacterial menaquinone and DNA

SU3327: A multi-target compound targeting bacterial menaquinone and DNA

  • Int J Antimicrob Agents. 2025 Nov 25;67(1):107679. doi: 10.1016/j.ijantimicag.2025.107679.
Shuge Wang 1,  Ke Zhao 1,  Ziqi Chen 1,  Chengtao Sun 1,  Hongliang Chen 2,  Yang Wang 3,  Congming Wu 4,  Dejun Liu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  • 2 School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiamen Vangenes Biotechnology CO., LTD, Xiamen, Fujian, China.
  • 3 State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: [email protected].
PMID: 41308844 DOI: 10.1016/j.ijantimicag.2025.107679
Abstract

Objectives: The rapid emergence of Antibiotic resistance (AMR) threatens global health by rendering existing Antibiotics ineffective, demanding novel antimicrobial agents with unique mechanisms of action. SU3327 (also known as Halicin), identified through deep learning-based drug screening, has demonstrated broad-spectrum Antibacterial activity and high safety in vivo. However, its precise mechanism of action remains unclear. This study aimed to elucidate the Antibacterial mechanism of SU3327 and to explore its potential as a multi-target therapeutic.

Methods: We employed microbiological, biochemical/biophysical, mass spectrometry, electrochemical, and transcriptomic analyses to study SU3327's effects. We examined its impact on proton motive force (PMF), intracellular ATP synthesis, and electron transport chain (ETC) function, including Complex I inhibition and menaquinone interaction. We also evaluated nitroreductase bioactivation, identified the hydroxylamine metabolite, and quantified resulting oxidative DNA damage.

Results: SU3327 disrupts Bacterial energy metabolism by targeting menaquinone (MK) in the ETC. It inhibits Complex I, impeding electron transfer, disrupting the PMF, and impairing ATP synthesis. Additionally, SU3327 enters Escherichia coli ATCC 25922, undergoing nitroreductase bioactivation, forming hydroxylamine compounds (R-NHOH) that react with DNA, generating hydroxyl radicals (•OH) and inducing oxidative DNA damage. These results indicate that SU3327 operates via a dual-target mechanism: disrupting Bacterial respiration and causing DNA damage.

Conclusions: SU3327 is a first-in-class multi-target Antibacterial agent acting via two synergistic mechanisms. Its dual action enhances efficacy and may reduce resistance likelihood by requiring mutations in distinct pathways. This study advances understanding of SU3327 and supports its development as a novel Antibiotic for veterinary medicine.

Keywords

ATP; DNA damage; Menaquinone; Nitrothiazoles; SU3327.

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