Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis
The N -sulfonated monobactams harbor considerable potential to combat emerging bacterial infections that are problematic to treat due to their metallo-β-lactamase mediated resistance against conventional β-lactam antibiotics. Herein, we report a divergent synthesis of C3-substituted 2,3-diaminopropi...
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Veröffentlicht in: | Chemical science (Cambridge) 2023-04, Vol.14 (14), p.3923-3931 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | The
N
-sulfonated monobactams harbor considerable potential to combat emerging bacterial infections that are problematic to treat due to their metallo-β-lactamase mediated resistance against conventional β-lactam antibiotics. Herein, we report a divergent synthesis of C3-substituted 2,3-diaminopropionates featuring an array of small functional groups and examine their potential as alternative precursors during monobactam biosynthesis in a mutant strain (
ΔsulG
) of
Pseudomonas acidophila
that is deficient in the supply of this native precursor.
In vitro
assays revealed high diastereoselectivity, as well as a substrate tolerance by the terminal adenylation domain of the non-ribosomal peptide synthetase (NRPS) SulM toward the majority of synthetic analogs. Chemical complementation of this mutant yielded a fluorinated, bioactive monobactam through fermentation as confirmed by a combination of spectrometric data and microbiological assays. This study demonstrates site-specific functionalization of a clinically important natural product and sets in place a platform for further strain improvements and engineered NRPS-biosynthesis of non-native congeners.
A small library of stereochemically-defined α,β-diamino acids has been prepared to generate non-native monobactams through fermentation, highlighting the potential of this platform for directed biosynthesis. |
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ISSN: | 2041-6520 2041-6539 |
DOI: | 10.1039/d2sc06893a |