Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV.

Autor:	Savage VJ; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK v.savage@redxpharma.com., Charrier C; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Salisbury AM; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Moyo E; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Forward H; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Chaffer-Malam N; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Metzger R; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Huxley A; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Kirk R; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Uosis-Martin M; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Noonan G; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Mohmed S; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Best SA; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Ratcliffe AJ; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK., Stokes NR; Redx Pharma, BioHub, Alderley Park, Cheshire SK10 4TG, UK.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2016 Jul; Vol. 71 (7), pp. 1905-13. Date of Electronic Publication: 2016 Mar 30.
DOI:	10.1093/jac/dkw061
Abstrakt:	Objectives: The objective of this study was to characterize the in vitro and in vivo biological properties of a novel series of small-molecule bacterial type IIA topoisomerase inhibitors. Methods: Bacterial susceptibility testing was performed by broth microdilution. Resistance frequencies were determined by plating bacteria onto agar containing test compound and enumerating mutants. Bacteria were passaged using subinhibitory concentrations of antibacterials to generate resistance. Target enzyme inhibition was determined by exposure to antibacterials and DNA; topoisomers were visualized by gel electrophoresis. Oral and intravenous pharmacokinetic profiles were determined in mice. In vivo efficacy was determined using a mouse model of septicaemia and thigh infection with MSSA and MRSA, respectively. Results: Representative compounds REDX04139, REDX05604 and REDX05931 demonstrated in vitro potency against a range of Gram-positive and fastidious Gram-negative pathogens. Clinical isolate testing revealed REDX04139 and REDX05931 had MIC90 values of 0.25 and 0.5 mg/L, respectively, for MRSA and MIC90 values of 2 mg/L for streptococci. REDX04139 was bactericidal in vitro against Staphylococcus aureus at 8× MIC over 6 h. Pharmacokinetic profiling of REDX04139 and REDX05604 in mice revealed low clearance and excellent bioavailability (≥71%). REDX04139 provided 100% survival against S. aureus in a mouse septicaemia model, while REDX05604 reduced bacterial load by up to 3.7 log units in the MRSA mouse thigh infection model. Conclusions: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria. (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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