5BS3

Crystal Structure of S.A. gyrase in complex with Compound 7

5BS3 の概要

• エントリーDOI: 10.2210/pdb5bs3/pdb
• 分子名称: DNA gyrase subunit A and B, DNA/RNA (5'-R(P*AP*GP*CP*CP*G)-D(P*T)-R(P*AP*GP*GP*GP*CP*CP*C)-D(P*T)-R(P*AP*CP*GP*GP*C)-D(P*T)-3'), MANGANESE (II) ION, ... (6 entities in total)
• 機能のキーワード: gyrase, antibacterial, sar, complex, isomerase-dna-rna complex, isomerase/dna/rna
• 由来する生物種: Staphylococcus aureus; 詳細
• 細胞内の位置: Cytoplasm : P20831
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 169871.33

構造登録者

Lu, J.,Patel, S.,Soisson, S. (登録日: 2015-06-01, 公開日: 2015-06-17, 最終更新日: 2024-03-06)

主引用文献

Singh, S.B.,Kaelin, D.E.,Wu, J.,Miesel, L.,Tan, C.M.,Black, T.,Nargund, R.,Meinke, P.T.,Olsen, D.B.,Lagrutta, A.,Lu, J.,Patel, S.,Rickert, K.W.,Smith, R.F.,Soisson, S.,Sherer, E.,Joyce, L.A.,Wei, C.,Peng, X.,Wang, X.,Fukuda, H.,Kishii, R.,Takei, M.,Takano, H.,Shibasaki, M.,Yajima, M.,Nishimura, A.,Shibata, T.,Fukuda, Y.
Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2).
Bioorg.Med.Chem.Lett., 25:1831-1835, 2015

PubMed Abstract: Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.

PubMed: 25851938
DOI: 10.1016/j.bmcl.2015.03.044

実験手法

X-RAY DIFFRACTION (2.65 Å)