title: Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode.
abstract: Bacterial resistance to antibiotics continues to pose serious challenges as the discovery rate for new antibiotics fades. Kibdelomycin is one of the rare, novel, natural product antibiotics discovered recently that inhibits the bacterial DNA synthesis enzymes gyrase and topoisomerase IV. It is a broad-spectrum, Gram-positive antibiotic without cross-resistance to known gyrase inhibitors, including clinically effective quinolones. To understand its mechanism of action, binding mode, and lack of cross-resistance, we have co-crystallized kibdelomycin and novobiocin with the N-terminal domains of Staphylococcus aureus gyrase B (24 kDa) and topo IV (ParE, 24 and 43 kDa). Kibdelomycin shows a unique "dual-arm", U-shaped binding mode in both crystal structures. The pyrrolamide moiety in the lower part of kibdelomycin penetrates deeply into the ATP-binding site pocket, whereas the isopropyl-tetramic acid and sugar moiety of the upper part thoroughly engage in polar interactions with a surface patch of the protein. The isoproramic acid (1,3-dioxopyrrolidine) and a tetrahydropyran acetate group (Sugar A) make polar contact with a surface area consisting of helix α4 and the flexible loop connecting helices α3 and α4. The two arms are connected together by a rigid decalin linker that makes van del Waals contacts with the protein backbone. This "dual-arm", U-shaped, multicontact binding mode of kibdelomycin is unique and distinctively different from binding modes of other known gyrase inhibitors (e.g., coumarins and quinolones), which explains its lack of cross-resistance and low frequency of resistance. The crystal structures reported in this paper should enable design and discovery of analogues with better properties and antibacterial spectrum.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Sangita
authors.initials: S
authors.lastname: Patel
authors.forename: Nandini
authors.initials: N
authors.lastname: Sharma
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Lumb
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D009675:Novobiocin / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D009281:Naphthalenes; D011758:Pyrroles; D011760:Pyrrolidinones; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; C000601708:kibdelomycin; C580577:kibdelomycin A; D009675:Novobiocin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase