Abstract
Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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DNA Gyrase / metabolism
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DNA Topoisomerase IV / antagonists & inhibitors
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DNA Topoisomerase IV / metabolism
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Dioxanes / chemical synthesis
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Dioxanes / chemistry
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Dioxanes / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Methicillin-Resistant Staphylococcus aureus / drug effects*
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Microbial Sensitivity Tests
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Molecular Structure
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Dioxanes
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Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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DNA Topoisomerase IV
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DNA Gyrase