title: Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors.
abstract: There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom. Electronic address: i.cooper@redxpharma.com.
authors: Ian R
authors: IR
authors: Cooper
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Andrew J
authors: AJ
authors: McCarroll
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: David
authors: D
authors: McGarry
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: James
authors: J
authors: Kirkham
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Mark
authors: M
authors: Pichowicz
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Rolf
authors: R
authors: Walker
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Catherine
authors: C
authors: Warrilow
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Anne-Marie
authors: AM
authors: Salisbury
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Victoria J
authors: VJ
authors: Savage
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Emmanuel
authors: E
authors: Moyo
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Henry
authors: H
authors: Forward
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Jonathan
authors: J
authors: Cheung
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Richard
authors: R
authors: Metzger
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Zoe
authors: Z
authors: Gault
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Gary
authors: G
authors: Nelson
authors: Department of Medical Biochemistry and Microbiology, Box 582 Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Diarmaid
authors: D
authors: Hughes
authors: Department of Medical Biochemistry and Microbiology, Box 582 Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Sha
authors: S
authors: Cao
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: John
authors: J
authors: Maclean
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Cédric
authors: C
authors: Charrier
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Mark
authors: M
authors: Craighead
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Stuart
authors: S
authors: Best
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Neil R
authors: NR
authors: Stokes
authors: Redx Pharma, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors: Andrew J
authors: AJ
authors: Ratcliffe
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; D053778:Thiazolidines; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Anti-infectives; DNA gyrase; ESKAPE pathogens; Isothiazolone; Topoisomerases