Solid-phase synthesis and biological evaluation of des-hydroxy pseudouridimycin analogs

  • ACS Med Chem Lett. 2026 Mar 11:10.1021/acsmedchemlett.5c00684. doi: 10.1021/acsmedchemlett.5c00684.
Avraz F Anwar  1 ,  Linlin You  2 ,  David Degen  2 ,  Katie J Burns  1 ,  Michael J Garza  1 ,  Richard H Ebright  2 ,  Juan R Del Valle  1
Affiliations
  • 1. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
  • 2. Waksman Institute and Department of Chemistry, Rutgers University, Piscataway, New Jersey 08854, United States.
PMID: 41890570 DOI: 10.1021/acsmedchemlett.5c00684
Abstract

Pseudouridimycin (PUM) is a C-nucleoside/peptide Antibiotic that selectively inhibits Bacterial RNA polymerase (RNAP) and exhibits potent activity against drug-resistant pathogens. However, PUM suffers from chemical instability due to self-immolative cleavage of its central hydroxamate bond. Here, we employed cryo-electron microscopy to determine structures of PUM (1) and a chemically stabilized des-hydroxy analog of PUM (2a) bound to an Escherichia coli RNAP transcription complex. Guided by the observed bound conformation, we developed an efficient solid-phase synthesis of 50 des-hydroxy PUM analogs modified at the Gln residue and Gdn-Gly tail. Several analogs retained low-micromolar RNAP-inhibitory activity, with a para-substituted phenyl amidine analog (54) emerging as the most potent inhibitor (IC50 = 0.95 μM). These results establish a versatile synthetic platform and structural framework for optimizing stabilized PUM derivatives and provide a foundation for the development of RNAP-targeted therapeutics against resistant Bacterial pathogens.

Keywords
RNA polymerase; antibiotics; nucleosides; peptidomimetics.
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