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Semi-synthesis and structure-activity relationship study yield antibacterial vicenistatin derivatives with low cytotoxicity

The Journal of Antibiotics volume 77, pages 221–227 (2024)Cite this article

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Abstract

Vicenistatin (1) is a 20-membered polyketide macrocyclic antibiotic with potent antimicrobial and cytotoxic activities. In this study, to further explore the potential of 1 as candidates of antibacterial drug development, 4’-N-demethyl vicenistatin (2), a secondary metabolite obtained from the ∆vicG mutant strain of Monodonata labio-associated Streptomyces parvus SCSIO Mla-L010, was utilized as a starting material for modifications of 4’-amino group of vicenistatin. Six new vicenistatin derivatives (3–8) were semi-synthesized through a concise route of amino modification with various aliphatic and aromatic aldehydes. Our study reveals that the bioactivity of vicenistatin is closely related to amino modification in sugar moiety, which results from the length of alkyl side chain as well as the presence of electron withdrawing/denoting group on the benzene ring. Importantly, compounds 4 with a butyl group and 8 with a 3,5-dihydroxyl-benzyl group at 4’-amino group, respectively, exhibited good antimicrobial activities, with MIC values spanning 0.5–4 μg ml−1 to Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Micrococcus luteus and Bacillus subtilis, with low cytotoxicity. This research promotes the further exploration of structure-activity relationships of vicenistatin and provides new vicenistatin derivatives for development of future anti-infectious agents with reduced cytotoxicity.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (42006103), Guangzhou Basic and Applied Basic Research Foundation (202201010336; 202201010519; 2023A04J1162), the Key-Area Research and Development Program of Guangdong Province (2020B1111030005), Open Project of Guangdong Key Laboratory of Marine Materia Medica (LMM2021-6), the Natural Science Foundation of Guangdong (2021B1515020036), the Nansha District Science and Technology Plan Project (NSJL202102), and Guangdong Provincial University Young Innovative Talents Project (2021KQNCX036). We acknowledge Professor Minggui Wang from Huashan Hospital, Professors Xiaoxiao Liu and Bing Gu from Guangdong Provincial People’s Hospital for the gifts of pathogenic bacteria.

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  1. These authors contributed equally: Jun Li, Zhenye Yang

Authors and Affiliations

  1. College of Light Industry and Food, Zhongkai University of Agriculture and Engineering, Guangzhou, 510225, China

    Jun Li

  2. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, Chinese Academy of Sceinces, South China Sea Institute of Oceanology, Guangzhou, 510301, China

    Jun Li, Zhenye Yang, Le Zhou, Qinglian Li & Jianhua Ju

  3. College of Oceanology, University of Chinese Academy of Sciences, Qingdao, 266400, China

    Zhenye Yang, Qinglian Li & Jianhua Ju

  4. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Chuanling Shi, Xiaoyun Wu & Yongqian Liang

  5. Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China

    Le Zhou, Qinglian Li & Jianhua Ju

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Correspondence to Qinglian Li or Jianhua Ju.

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Li, J., Yang, Z., Shi, C. et al. Semi-synthesis and structure-activity relationship study yield antibacterial vicenistatin derivatives with low cytotoxicity. J Antibiot 77, 221–227 (2024). https://doi.org/10.1038/s41429-023-00701-3

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