title: Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus.
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.
authors.affiliation: Infectious Diseases, Merck Research Laboratories, Merck & Co, Rahway, NJ 07065, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goetz
authors.forename: Scott K
authors.initials: SK
authors.lastname: Smith
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Jon
authors.initials: J
authors.lastname: Polishook
authors.forename: Russell
authors.initials: R
authors.lastname: Onishi
authors.forename: Scott
authors.initials: S
authors.lastname: Salowe
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.forename: John
authors.initials: J
authors.lastname: Allocco
authors.forename: Janet
authors.initials: J
authors.lastname: Sigmund
authors.forename: Karen
authors.initials: K
authors.lastname: Dorso
authors.forename: Suzy
authors.initials: S
authors.lastname: Lee
authors.forename: Stephen
authors.initials: S
authors.lastname: Skwish
authors.forename: Mercedes
authors.initials: M
authors.lastname: de la Cruz
authors.forename: Jesús
authors.initials: J
authors.lastname: Martín
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Painter
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Karen
authors.initials: K
authors.lastname: Overbye
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000192:Actinomycetales / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011758:Pyrroles; D011760:Pyrrolidinones; D059005:Topoisomerase II Inhibitors; C000601708:kibdelomycin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase