6TCK

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

Summary for 6TCK

• Entry DOI: 10.2210/pdb6tck/pdb
• Descriptor: 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)
• Functional Keywords: dna gyrase, gyrb, isomerase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 2
• Total formula weight: 49757.04

Authors

Welin, M.,Kimbung, R.,Focht, D. (deposition date: 2019-11-06, release date: 2020-09-23, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)