Work

Solid-Phase Synthesis and Biological Evaluation of Des-hydroxy Pseudouridimycin Analogs

Year: 2026

Type: article

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 (IC 50 = 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00684