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Osheroff Lab

Antibacterial Resistance

Fluoroquinolones are one of the most important classes of broad-spectrum antibacterial drugs in clinical use. This antibacterial class stabilizes DNA strand breaks generated by the bacterial type II topoisomerases, gyrase and topoisomerase IV. The clinical efficacy of these agents is threatened by growing resistance associated with mutations in gyrase and/or topoisomerase IV. Topoisomerase-fluoroquinolone interactions and the mechanism by which specific mutations in the enzymes cause resistance are not well characterized. A thorough understanding of fluoroquinolone actions and resistance mechanisms will inform the design of novel drugs that retain activity against resistant strains. Novel bacterial topoisomerase inhibitors (NBTIs) and spiropyrimidinetriones (SPTs) are two classes of compounds targeted toward bacterial type II topoisomerases that can overcome fluoroquinolone resistance.

CURRENT PROJECTS ON ANTIBACTERIAL MECHANISM AND RESISTANCE:

  • Determining the mechanistic basis of fluoroquinolone resistance in E. coli and N. gonorrhoeae.
  • Determining the relative contributions of topoisomerase IV and gyrase to fluoroquinolone action in the bacterial cell.
  • Designing novel fluoroquinolones, NBTIs, and SPTs that overcome common resistance mutations.
  • Characterizing interactions between NBTIs and A. baumannii, E. coli and N. gonorrhoeae gyrase and topoisomerase IV.
  • Characterizing interactions between SPTs and A. baumannii, M. tuberculosis, and N. gonorrhoeae type II topoisomerases.