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

SummaryBacterial 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.

Graphical AbstractFigure optionsDownload high-quality image (394 K)Download as PowerPoint slideHighlights
► Chemical genetic profiling of natural products accelerates antibiotic discovery
► Identification of a new class of antibiotics from a new member of Kibdelosporangium
► Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity
► Kibdelomycin is a potent inhibitor of bacterial type II topoisomerases