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

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. Strategic modification of the guanidine tail and central hydroxamate bond in the antibacterial natural product pseudouridimycin (PUM) dramatically enhances its chemical stability. Three hydroxamate-modified analogues retain much of the antibacterial activity of PUM despite reduced RNAP-inhibitory activity. Stabilization of the hydroxamate C-N bond in PUM represents a viable strategy toward clinically relevant analogues.image

Automated summary

Pseudouridimycin (PUM) is a promising drug but suffers from rapid decomposition. Researchers have successfully stabilized PUM by modifying its structure, and certain analogues with modifications still retain antibacterial activity.