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Apr 05, 2023;14 (14): 3923-3931.

Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis.

Michael S Lichstrahl, Lukas Kahlert, Rongfeng Li, Trevor A Zandi, Jerry Yang, Craig A Townsend
Author Information
  1. Michael S Lichstrahl: Department of Chemistry, The Johns Hopkins University 3400 N Charles St Baltimore MD USA ctownsend@jhu.edu. ORCID
  2. Lukas Kahlert: Department of Chemistry, The Johns Hopkins University 3400 N Charles St Baltimore MD USA ctownsend@jhu.edu. ORCID
  3. Rongfeng Li: Department of Chemistry, The Johns Hopkins University 3400 N Charles St Baltimore MD USA ctownsend@jhu.edu. ORCID
  4. Trevor A Zandi: Novartis Institutes for Biomedical Research Cambridge MA USA. ORCID
  5. Jerry Yang: Department of Chemistry, The Johns Hopkins University 3400 N Charles St Baltimore MD USA ctownsend@jhu.edu.
  6. Craig A Townsend: Department of Chemistry, The Johns Hopkins University 3400 N Charles St Baltimore MD USA ctownsend@jhu.edu. ORCID
PMID: 37035696 DOI: 10.1039/d2sc06893a

Abstract

The -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 () of that is deficient in the supply of this native precursor. 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.

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Grants

  1. R01 AI121072/NIAID NIH HHS
Journal Article
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