Semi-synthesis and structure-activity relationship study yield antibacterial vicenistatin derivatives with low cytotoxicity
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...
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Published in | Journal of antibiotics Vol. 77; no. 4; pp. 221 - 227 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Tokyo
Springer Japan
01.04.2024
Springer Nature Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-8820 1881-1469 |
DOI: | 10.1038/s41429-023-00701-3 |