3U2K

S. aureus GyrB ATPase domain in complex with a small molecule inhibitor

Summary for 3U2K

• Entry DOI: 10.2210/pdb3u2k/pdb
• Related: 3TTZ 3U2D
• Descriptor: DNA gyrase subunit B, 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyridine-4-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: protein-inhibitor complex, atp-binding, structure-based drug design, antimicrobial, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Staphylococcus aureus; More
• Cellular location: Cytoplasm : P0A0K8
• Total number of polymer chains: 2
• Total formula weight: 46097.70

Authors

Boriack-Sjodin, P.A.,Prince, D.B.,Eakin, A.E.,Sherer, B.A. (deposition date: 2011-10-03, release date: 2012-01-11, Last modification date: 2024-02-28)

Primary citation

Eakin, A.E.,Green, O.,Hales, N.,Walkup, G.K.,Bist, S.,Singh, A.,Mullen, G.,Bryant, J.,Embrey, K.,Gao, N.,Breeze, A.,Timms, D.,Andrews, B.,Uria-Nickelsen, M.,Demeritt, J.,Loch, J.T.,Hull, K.,Blodgett, A.,Illingworth, R.N.,Prince, B.,Boriack-Sjodin, P.A.,Hauck, S.,Macpherson, L.J.,Ni, H.,Sherer, B.
Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents.
Antimicrob.Agents Chemother., 56:1240-1246, 2012

PubMed Abstract: DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified by a fragment-based lead generation (FBLG) approach using nuclear magnetic resonance (NMR) screening to identify low-molecular-weight compounds that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding constant of 1 mM formed the basis of the design and synthesis of a focused library of compounds that resulted in the rapid identification of a lead compound that inhibited DNA gyrase with a 50% inhibitory concentration (IC(50)) of 3 μM. The potency of the lead compound was further optimized by utilizing iterative X-ray crystallography to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates containing pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compounds was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clinical indications.

PubMed: 22183167
DOI: 10.1128/AAC.05485-11

Experimental method

X-RAY DIFFRACTION (1.64 Å)