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- Title
A Boron‐Dependent Antibiotic Derived from a Calcium‐Dependent Antibiotic.
- Authors
Chiou, Shao‐Lun; Chen, Yi‐Ju; Lee, Chu‐Ting; Ho, Minh Ngoc; Miao, Jiayuan; Kuo, Po‐Cheng; Hsu, Cheng‐Chih; Lin, Yu‐Shan; Chu, John
- Abstract
The prevalence of drug‐resistant bacterial pathogens foreshadows a healthcare crisis. Calcium‐dependent antibiotics (CDAs) are promising candidates to combat infectious diseases as many of them show modes of action (MOA) orthogonal to widespread resistance mechanisms. The calcium dependence is nonetheless one of the hurdles toward realizing their full potential. Using laspartomycin C (LspC) as a model, we explored the possibility of reducing, or even eliminating, its calcium dependence. We report herein a synthetic LspC analogue (B1) whose activity no longer depends on calcium and is instead induced by phenylboronic acid (PBA). In LspC, Asp1 and Asp7 coordinate to calcium to anchor it in the active conformation; these residues are replaced by serine in B1 and condense with PBA to form a boronic ester with the same anchoring effect. Using thin‐layer chromatography, MS, NMR, and complementation assays, we demonstrate that B1 inhibits bacterial growth via the same MOA as LspC, i.e. sequestering the cell wall biosynthetic intermediate undecaprenyl phosphate. B1 is as potent and effective as LspC against several Gram‐positive bacteria, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus. Our success in converting a CDA to a boron‐dependent antibiotic opens a new avenue in the design and functional control of drug molecules.
- Subjects
METHICILLIN-resistant staphylococcus aureus; ANCHORING effect; ANTIBIOTICS; CONTROL (Psychology); BORONIC esters; LINEZOLID; BORON
- Publication
Angewandte Chemie, 2024, Vol 136, Issue 5, p1
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.202317522