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  3. Design and synthesis of fascaplysin derivatives as inhibitors of FtsZ with potent antibacterial activity and mechanistic study

Design and synthesis of fascaplysin derivatives as inhibitors of FtsZ with potent antibacterial activity and mechanistic study

  • Eur J Med Chem. 2023 Jun 5;254:115348. doi: 10.1016/j.ejmech.2023.115348.
Hongda Qiu 1,  Xing Zhao 1,  Yinli Jiang 1,  Weida Liang 1,  Weile Wang 1,  Xingyao Jiang 1,  Mengying Jiang 1,  Xiao Wang 2,  Wei Cui 3,  Yang Li 4,  Keqi Tang 5,  Tao Zhang 6,  Lingling Zhao 1,  Hongze Liang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China.
  • 2 School of Medicine, Ningbo University, Ningbo, 315211, China. Electronic address: [email protected].
  • 3 School of Medicine, Ningbo University, Ningbo, 315211, China.
  • 4 Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China.
  • 5 Institute of Mass Spectrometry, School of Materials Science & Chemical Engineering, Ningbo University, Ningbo, 315211, China.
  • 6 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, and College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 7 Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China. Electronic address: [email protected].
PMID: 37060755 DOI: 10.1016/j.ejmech.2023.115348
Abstract

The increase in Antibiotic resistance has made it particularly urgent to develop new Antibiotics with novel Antibacterial mechanisms. Inhibition of Bacterial cell division by disrupting filamentous temperature-sensitive mutant Z (FtsZ) function is an effective and promising approach. A series of novel fascaplysin derivatives with tunable hydrophobicity were designed and synthesized here. The in vitro bioactivity assessment revealed that these compounds could inhibit the tested Gram-positive bacteria including methicillin-resistant S. aureus (MRSA) (MIC = 0.049-25 μg/mL), B. subtilis (MIC = 0.024-12.5 μg/mL) and S. pneumoniae (MIC = 0.049-50 μg/mL). Among them, compounds B3 (MIC = 0.098 μg/mL), B6 (MIC = 0.098 μg/mL), B8 (MIC = 0.049 μg/mL) and B16 (MIC = 0.098 μg/mL) showed the best bactericidal activities against MRSA and no significant tendency to trigger Bacterial resistance as well as rapid bactericidal properties. The cell surface integrity of bacteria was significantly disrupted by hydrophobic tails of fascaplysin derivatives. Further studies revealed that these highly active amphiphilic compounds showed low hemolytic activity and cytotoxicity to mammalian cells. Preliminary mechanistic exploration suggests that B3, B6, B8 and B16 are potent FtsZ inhibitors to promote FtsZ polymerization and inhibit GTPase activity of FtsZ, leading to the death of Bacterial cells by inhibiting Bacterial division. Molecular docking simulations and structure-activity relationship (SAR) study reveal that appropriate increase in the hydrophobicity of fascaplysin derivatives and the addition of additional hydrogen bonds facilitated their binding to FtsZ proteins. These amphiphilic fascaplysin derivatives could serve as a novel class of FtsZ inhibitors, which not only gives new prospects for the application of compounds containing this skeleton but also provides new ideas for the discovery of new Antibiotics.

Keywords

Antibacterial; Bacterial resistance; Fascaplysin; FtsZ inhibitor; Marine drugs.

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