In vitro biological evaluation of novel broad-spectrum isothiazolone inhibitors of bacterial type II topoisomerases

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Charrier, Cédric and Salisbury, Anne-Marie and Savage, Victoria J. and Moyo, Emmanuel and Forward, Henry and Ooi, Nicola and Cheung, Jonathan and Metzger, Richard and McGarry, David and Walker, Rolf and Cooper, Ian R. and Ratcliffe, Andrew J. and Stokes, Neil R. (2016) In vitro biological evaluation of novel broad-spectrum isothiazolone inhibitors of bacterial type II topoisomerases. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453 (https://doi.org/10.1093/jac/dkw228)

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Abstract

OBJECTIVES: To evaluate the in vitro biological properties of a novel class of isothiazolone inhibitors of the bacterial type II topoisomerases. METHODS: Inhibition of DNA gyrase and topoisomerase IV activity was assessed using DNA supercoiling and decatenation assays. MIC and MBC were determined according to CLSI guidelines. Antibacterial combinations were assessed using a two-dimensional chequerboard MIC method. Spontaneous frequency of resistance was measured at various multiples of the MIC. Resistant mutants were generated by serial passage at subinhibitory concentrations of antibacterials and genetic mutations were determined through whole genome sequencing. Mammalian cytotoxicity was evaluated using the HepG2 cell line. RESULTS: Representative isothiazolone compound REDX04957 and its enantiomers (REDX05967 and REDX05990) showed broad-spectrum bactericidal activity against the ESKAPE organisms, with the exception of Enterococcus spp., as well as against a variety of other human bacterial pathogens. Compounds retained activity against quinolone-resistant strains harbouring GyrA S83L and D87G mutations (MIC ≤4 mg/L). Compounds inhibited the supercoiling activity of wild-type DNA gyrase and the decatenation function of topoisomerase IV. Frequency of resistance of REDX04957 at 4× MIC was <9.1 × 10(-9). Against a panel of recent MDR isolates, REDX05967 demonstrated activity against Acinetobacter baumannii with MIC50 and MIC90 of 16 and 64 mg/L, respectively. Compounds showed a lack of cytotoxicity against HepG2 cells at 128 mg/L. CONCLUSIONS: Isothiazolone compounds show potent activity against Gram-positive and -negative pathogens with a dual targeting mechanism-of-action and a low potential for resistance development, meriting their continued investigation as broad-spectrum antibacterial agents.

ORCID iDs

Charrier, Cédric, Salisbury, Anne-Marie, Savage, Victoria J., Moyo, Emmanuel, Forward, Henry, Ooi, Nicola, Cheung, Jonathan, Metzger, Richard, McGarry, David ORCID logoORCID: https://orcid.org/0000-0002-7087-0584, Walker, Rolf, Cooper, Ian R., Ratcliffe, Andrew J. and Stokes, Neil R.;
  • Item type:Article
    ID code:57161
    Dates:
    Date
    Event
    26 June 2016
    Published
    26 June 2016
    Published Online
    13 May 2016
    Accepted
    Notes:This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record Charrier, C., Salisbury, A-M., Savage, V. J., Moyo, E., Forward, H., Ooi, N., ... Stokes, N. R. (2016). In vitro biological evaluation of novel broad-spectrum isothiazolone inhibitors of bacterial type II topoisomerases. Journal of Antimicrobial Chemotherapy is available online at: https://dx.doi.org10.1093/jac/dkw228
    Subjects:Medicine > Therapeutics. Pharmacology
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:28 Jul 2016 09:34
    Last modified:27 Nov 2024 01:11
    URI:https://strathprints.strath.ac.uk/id/eprint/57161
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