Discovery of Kibdelomycin, a Potent New Class of Bacterial Type II Topoisomerase Inhibitor by Chemical-Genetic Profiling in Staphylococcus Aureus

Chem Biol. 2011 Aug 26;18(8):955-65. doi: 10.1016/j.chembiol.2011.06.011.

Abstract

Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades.

MeSH terms

  • Actinomycetales / chemistry*
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / isolation & purification
  • Anti-Bacterial Agents / pharmacology*
  • DNA Gyrase / metabolism
  • DNA Topoisomerase IV / antagonists & inhibitors
  • DNA Topoisomerase IV / metabolism
  • Drug Resistance, Bacterial
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Pyrroles / chemistry*
  • Pyrroles / isolation & purification
  • Pyrroles / pharmacology*
  • Pyrrolidinones / chemistry*
  • Pyrrolidinones / isolation & purification
  • Pyrrolidinones / pharmacology*
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / enzymology*
  • Staphylococcus aureus / genetics
  • Topoisomerase II Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / isolation & purification
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Pyrroles
  • Pyrrolidinones
  • Topoisomerase II Inhibitors
  • kibdelomycin
  • DNA Topoisomerase IV
  • DNA Gyrase