6TCK

Crystal structure of the ATP binding domain of S. aureus GyrB complexed with ULD-2

6TCK の概要

• エントリーDOI: 10.2210/pdb6tck/pdb
• 分子名称: DNA gyrase subunit B, 2-[[3,4-bis(chloranyl)-5-methyl-1~{H}-pyrrol-2-yl]carbonylamino]-4-phenylmethoxy-1,3-benzothiazole-6-carboxylic acid, GLYCEROL, ... (9 entities in total)
• 機能のキーワード: dna gyrase, gyrb, isomerase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49757.04

構造登録者

Welin, M.,Kimbung, R.,Focht, D. (登録日: 2019-11-06, 公開日: 2020-09-23, 最終更新日: 2024-01-24)

主引用文献

Nyerges, A.,Tomasic, T.,Durcik, M.,Revesz, T.,Szili, P.,Draskovits, G.,Bogar, F.,Skok, Z.,Zidar, N.,Ilas, J.,Zega, A.,Kikelj, D.,Daruka, L.,Kintses, B.,Vasarhelyi, B.,Foldesi, I.,Kata, D.,Welin, M.,Kimbung, R.,Focht, D.,Masic, L.P.,Pal, C.
Rational design of balanced dual-targeting antibiotics with limited resistance.
Plos Biol., 18:e3000819-e3000819, 2020

PubMed Abstract: Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections.

PubMed: 33017402
DOI: 10.1371/journal.pbio.3000819

実験手法

X-RAY DIFFRACTION (1.6 Å)