Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes Journal Article


Authors: Davis, T. D.; Mohandas, P.; Chiriac, M. I.; Bythrow, G. V.; Quadri, L. E. N.; Tan, D. S.
Article Title: Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes
Abstract: Biosynthesis of bacterial natural-product virulence factors is emerging as a promising antibiotic target. Many such natural products are produced by nonribosomal peptide synthetases (NRPS) from amino acid precursors. To develop selective inhibitors of these pathways, we have previously described aminoacyl-AMS (sulfamoyladenosine) macrocycles that inhibit NRPS amino acid adenylation domains but not mechanistically-related aminoacyl-tRNA synthetases. To improve the cell permeability of these inhibitors, we explore herein replacement of the α-amino group with an α-hydroxy group. In both macrocycles and corresponding linear congeners, this leads to decreased biochemical inhibition of the cysteine adenylation domain of the Yersina pestis siderophore synthetase HMWP2, which we attribute to loss of an electrostatic interaction with a conserved active-site aspartate. However, inhibitory activity can be regained by installing a cognate β-thiol moiety in the linear series. This provides a path forward to develop selective, cell-penetrant inhibitors of the biosynthesis of virulence factors to probe their biological functions and potential as therapeutic targets. © 2016 Elsevier Ltd
Keywords: adenylation; virulence; antibiotic; rational design; non-ribosomal peptide synthetase
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 26
Issue: 21
ISSN: 0960-894X
Publisher: Pergamon-Elsevier Science Ltd  
Date Published: 2016-11-01
Start Page: 5340
End Page: 5345
Language: English
DOI: 10.1016/j.bmcl.2016.09.027
PROVIDER: scopus
PMCID: PMC5079767
PUBMED: 27692545
DOI/URL:
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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MSK Authors
  1. Derek S Tan
    68 Tan
  2. Tony Davis
    2 Davis