We have discovered a structurally novel series of inhibitors of bacterial topoisomerases in Gram-positive organisms.  In addition to potent in vitro activity against these precedented targets, the inhibitors possess compelling whole cell activity, with MIC90 values of 0.25 mg/mL or lower against critical pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes.  In vivo activity against multiple pathogens in both systemic and tissue-based murine models of infection has also been demonstrated.  Our studies also included the elucidation of resistance mechanisms to these novel compounds.  This understanding was further enhanced using a variety of techniques, including spontaneous mutation frequencies, mutant prevention concentrations (MPCs), and hollow-fiber models aimed at understanding the role of pharmacokinetic/phamacodynamic (PK/PD) relationships in resistance emergence.  This talk will provide an overview of chemical, biological, pharmacokinetic, and toxicological properties using data from illustrative examples

Novel, non-quinolone inhibitors of DNA gyrase and topoisomerase IV: Antibacterial activity and resistance mechanisms

243rd National Meeting (2012)

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