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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Dioxanes/pharmacology , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/metabolism , Dioxanes/chemical synthesis , Dioxanes/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
We evaluated different susceptibility testing media against 200 Klebsiella pneumoniae isolates that have been genetically characterized for the presence of polymyxin resistance mechanisms. The media evaluated included calcium enriched media that was described to promote separation of mcr-carrying Enterobacterales isolates and standard cation-adjusted Mueller-Hinton broth with and without polysorbate 80. The testing conditions evaluated did not show improvement in the separation of isolates carrying MgrB alterations and other mutation-driven polymyxin resistance mechanisms.
