Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide‐Modified Analogues
-
Published:2023-10-06
Issue:1
Volume:19
Page:
-
ISSN:1860-7179
-
Container-title:ChemMedChem
-
language:en
-
Short-container-title:ChemMedChem
Author:
Anwar Avraz F.1,
Cain Christopher F.1,
Garza Michael J.1,
Degen David2,
Ebright Richard H.2,
Del Valle Juan R.1
Affiliation:
1. Department of Chemistry and Biochemistry University of Notre Dame Notre Dame, IN 46556 USA
2. Waksman Institute and Department of Chemistry Rutgers University Piscataway, NJ 08854 USA
Abstract
AbstractPseudouridimycin (PUM) is a microbially produced C‐nucleoside dipeptide that selectively targets the nucleotide addition site of bacterial RNA polymerase (RNAP) and that has a lower rate of spontaneous resistance emergence relative to current drugs that target RNAP. Despite its promising biological profile, PUM undergoes relatively rapid decomposition in buffered aqueous solutions. Here, we describe the synthesis, RNAP‐inhibitory activity, and antibacterial activity of chemically stabilized analogues of PUM. These analogues feature targeted modifications that mitigate guanidine‐mediated hydroxamate bond scission. A subset of analogues in which the central hydroxamate is replaced with amide or hydrazide isosteres retain the antibacterial activity of the natural product.
Funder
National Science Foundation
National Institutes of Health
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology