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

• Published in: Journal of antibiotics Vol. 77; no. 4; pp. 221 - 227
• Main Authors: Li, Jun, Yang, Zhenye, Shi, Chuanling, Wu, Xiaoyun, Zhou, Le, Liang, Yongqian, Li, Qinglian, Ju, Jianhua
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.04.2024; Springer Nature; Nature Publishing Group
• Subjects: 631/154/309/2144; 631/154/309/2419; 631/326/22/1290; Aldehydes; Aminoglycosides; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - pharmacology; Bacteriology; Benzene; Biocompatibility; Biological activity; Biomedical and Life Sciences; Bioorganic Chemistry; Biotechnology & Applied Microbiology; Cytotoxicity; Drug development; Drug resistance; Immunology; Lactams; Life Sciences; Life Sciences & Biomedicine; Macrolides; Medicinal Chemistry; Metabolites; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbiology; Organic Chemistry; Pharmacology & Pharmacy; Science & Technology; Semisynthesis; Staphylococcus infections; Structure-Activity Relationship; Structure-activity relationships; Toxicity; STARTER UNIT; AGLYCON; CRYSTAL-STRUCTURE; BIOSYNTHESIS
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-023-00701-3

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.