1. Biological evaluation of benzothiazole ethyl urea inhibitors of bacterial type II topoisomerases
- Author
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Stephanie Barker, Ian Collins, Carol Smee, Neil R. Stokes, Vicki Gamble, David J. Haydon, James M. Bennett, Lloyd George Czaplewski, Stéphanie Pommier, Daniel J. Price, Christopher J. Lunniss, Alastair Logan, Hilary Peasley, Paul Lancett, Joanne Berry, and Helena Thomaides-Brears
- Subjects
DNA Topoisomerase IV ,Male ,Topoisomerase IV ,medicine.drug_class ,Cell Survival ,Topoisomerase Inhibitors ,Gene Expression ,Levofloxacin ,Microbial Sensitivity Tests ,medicine.disease_cause ,Gram-Positive Bacteria ,DNA gyrase ,Microbiology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Bacterial Proteins ,Gram-Negative Bacteria ,medicine ,Escherichia coli ,Animals ,Humans ,Urea ,Pharmacology (medical) ,Experimental Therapeutics ,Benzothiazoles ,Novobiocin ,Pharmacology ,Adenosine Triphosphatases ,biology ,Topoisomerase ,Interleukins ,Hep G2 Cells ,biochemical phenomena, metabolism, and nutrition ,Interleukin-33 ,Recombinant Proteins ,Anti-Bacterial Agents ,Rats ,Infectious Diseases ,DNA Topoisomerases, Type II ,Benzothiazole ,chemistry ,Staphylococcus aureus ,biology.protein ,DNA supercoil ,Topoisomerase inhibitor ,medicine.drug - Abstract
The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of Clostridium difficile , and selected Gram-negative respiratory pathogens. MIC 90 s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus . No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were −10 with compound A and −11 with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.
- Published
- 2013