title: Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria.
abstract: The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of thein vitroproperties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities ofEscherichia coliDNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms andMycobacterium tuberculosisNo cross-resistance with fluoroquinolone-resistantStaphylococcus aureusandE. coliisolates was observed. Measured MIC90values were 4 and 8 μg/ml against a panel of contemporary multidrug-resistant isolates ofAcinetobacter baumanniiandE. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically <10-8againstE. coliandA. baumanniiat concentrations equivalent to 4-fold the MIC. Compound-resistantE. colimutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminaryin vitrosafety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC50], >100 μM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorablein vitrosafety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Cédric
authors.initials: C
authors.lastname: Charrier
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom am.salisbury@redxpharma.com.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Salisbury
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Savage
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duffy
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moyo
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Nathan
authors.initials: N
authors.lastname: Chaffer-Malam
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ooi
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Newman
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Metzger
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: McGarry
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Pichowicz
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Ralph
authors.initials: R
authors.lastname: Sigerson
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Cooper
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Nelson
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Butler
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Craighead
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ratcliffe
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Best
authors.affiliation: Redx Pharma, Alderley Park, Cheshire, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Stokes
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D002939:Ciprofloxacin; D027101:DNA Topoisomerase IV
keywords: DNA gyrase; ESKAPE; antibiotic; topoisomerase