A Boron‐Dependent Antibiotic Derived from a Calcium‐Dependent Antibiotic

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 nonet...

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Bibliographic Details
Published in:Angewandte Chemie 2024-01, Vol.136 (5), p.n/a
Main 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
Format: Article
Language:English
Subjects:
Antibiotics
Bacteria
Boron
Boron-Dependent Antibiotic
Calcium
Calcium-Dependent Antibiotic
Cell walls
Chemistry
Conformation
Drug development
Drug-Resistant Bacteria
Infectious diseases
Laspartomycin
Methicillin
NMR
Nuclear magnetic resonance
Phenylboronic Acid
Public health
Sequestering
Vancomycin
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Summary: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. The side‐chain carboxylates of Asp1 and Asp7 in laspartomycin coordinate with a calcium cation to adopt the active conformation. When these residues were replaced by serine, calcium dependence was eliminated and the resulting synthetic analogue depended instead on phenylboronic acid for its antimicrobial activity.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202317522