Comprehensive analysis of the antibacterial activity of 5,8-dihydroxy-1,4-naphthoquinone derivatives against methicillin-resistant Staphylococcus aureus.

Qingqing CHEN; Yuhang DING; Zhongyi LI; Xingyu CHEN; Aliya FAZAL; Yahan ZHANG; Yudi MA; Changyi WANG; Liu YANG; Tongming YIN; Guihua LU; Hongyan LIN; Zhongling WEN; Jinliang QI; Hongwei HAN; Yonghua YANG

Return

Comprehensive analysis of the antibacterial activity of 5,8-dihydroxy-1,4-naphthoquinone derivatives against methicillin-resistant Staphylococcus aureus.

Author: Qingqing CHEN ¹ ; Yuhang DING ¹ ; Zhongyi LI ¹ ; Xingyu CHEN ² ; Aliya FAZAL ¹ ; Yahan ZHANG ² ; Yudi MA ² ; Changyi WANG ² ; Liu YANG ² ; Tongming YIN ³ ; Guihua LU ¹ ; Hongyan LIN ⁴ ; Zhongling WEN ⁵ ; Jinliang QI ⁶ ; Hongwei HAN ⁷ ; Yonghua YANG ⁸
Author Information

1. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
2. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
3. Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
4. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China; School of Pharmacy, Changzhou University, Changzhou 213164, China.
5. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: wenzhongling@nju.edu.cn.
6. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: qijl@nju.edu.cn.
7. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: hanhw18@nju.edu.cn.
8. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: yangyh@nju.edu.cn.
Publication Type:Journal Article
Keywords: 5,8-Dihydroxy-1,4-naphthoquinone; Antibacterial activity; Arginine biosynthesis; MRSA; Pyrimidine metabolism
MeSH: Methicillin-Resistant Staphylococcus aureus/genetics*; Anti-Bacterial Agents/chemistry*; Naphthoquinones/administration & dosage*; Animals; Microbial Sensitivity Tests; Mice; Humans; Staphylococcal Infections/microbiology*; Molecular Structure
From: Chinese Journal of Natural Medicines (English Ed.) 2025;23(5):604-613
CountryChina
Language:English
Abstract: Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.