Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide-Modified Analogues

Avraz F. Anwar; Christopher F. Cain; Michael J. Garza; David Degen; Richard H. Ebright; Juan R. Del Valle

doi:10.1002/cmdc.202300474

Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide-Modified Analogues

Avraz F. Anwar, Christopher F. Cain, Michael J. Garza, David Degen, Richard H. Ebright, Juan R. Del Valle

Waksman Institute of Microbiology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Pseudouridimycin (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.

Original language	American English
Article number	e202300474
Journal	ChemMedChem
Volume	19
Issue number	1
DOIs	https://doi.org/10.1002/cmdc.202300474
State	Published - Jan 2 2024

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Organic Chemistry

Keywords

RNA polymerase
antibiotics
nucleosides
peptidomimetics

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10.1002/cmdc.202300474

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abstract = "Pseudouridimycin (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.",

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AU - Degen, David

AU - Ebright, Richard H.

AU - Del Valle, Juan R.

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AB - Pseudouridimycin (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.

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KW - nucleosides

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Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide-Modified Analogues

Abstract

ASJC Scopus subject areas

Keywords

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