and Properties of CUO246, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2022 Nov 30

PMID 36448795

Authors

Johanne Blais

Charles R Dean

Guillaume Lapointe

Jennifer A Leeds

Sylvia Ma

Laura Morris

Heinz E Moser

Colin S Osborne

Katherine R Prosen

Daryl Richie

Colin Skepper

Katherine Thompson

Jason Vo

Qin Yue

Alexey Rivkin

Affiliations

Soon will be listed here.

Abstract

CUO246, a novel DNA gyrase/topoisomerase IV inhibitor, is active against a broad range of Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens and retains activity against quinolone-resistant strains in circulation. The frequency of selection for single step mutants of wild-type S. aureus with reduced susceptibility to CUO246 was <4.64 × 10 at 4× and 8× MIC and remained low when using an isogenic QRDR mutant (<5.24 × 10 at 4× and 8× MIC). Biochemical assays indicated that CUO246 had potent inhibitory activity against both DNA gyrase (GyrAB) and topoisomerase IV (ParCE). Furthermore, CUO246 showed rapid bactericidal activity in time-kill assays and potent efficacy against S. aureus in a neutropenic murine thigh infection model. These results suggest that CUO246 may be useful in treating infections by various causative agents of acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.

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