2. Academic Validation
  3. Design, synthesis of griseofamine A derivatives and development of potent antibacterial agents against MRSA

Design, synthesis of griseofamine A derivatives and development of potent antibacterial agents against MRSA

  • Eur J Med Chem. 2024 Oct 5:276:116703. doi: 10.1016/j.ejmech.2024.116703.
Caiyun Ma 1,  Rao Wei 1,  Rui Yu 1,  Ling Lei 1,  Xuan Pan 2,  Hai-Yu Hu 3,  Bo Feng 4,  Zhanzhu Liu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: panxuan@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: haiyu.hu@imm.ac.cn.
  • 4 Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, PR China. Electronic address: 973502794@qq.com.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: liuzhanzhu@imm.ac.cn.
PMID: 39059183 DOI: 10.1016/j.ejmech.2024.116703
Abstract

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA), one of the most important multidrug-resistant bacteria in clinic, has become a serious global health issue. In this study, we designed and synthesized a series of griseofamine A derivatives and evaluated their Antibacterial profiles. In vitro assays found that compound 9o10 showed a remarkable improvement of Antibacterial activity toward MRSA (MIC = 0.0625 μg/mL), compared with griseofamine A (MIC = 8 μg/mL) and vancomycin (MIC = 0.5 μg/mL) with low hemolysis and cytotoxicity. Its rapid bactericidal property was also confirmed by time-kill curve assay. Furthermore, compound 9o10 displayed weak drug resistance frequency. In in vivo experiment, compound 9o10 exhibited more potent Antibacterial efficacy than vancomycin and excellent biosafety (LD50 > 2 g/kg). Preliminary mechanism study revealed compound 9o10 might involve Antibacterial mechanisms contributing to membrane damage. Taken together, compound 9o10 possessed excellent inhibitory activity against MRSA in vitro and in vivo with low toxicity and drug resistance frequency, making it a promising hit compound for further development against MRSA infections.

Keywords

Antibacterial; Griseofamine a; MRSA; Natural product; Structural modification.

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