7LHZ

K. pneumoniae Topoisomerase IV (ParE-ParC) in complex with DNA and (3S)-10-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-9-fluoro-3-methyl-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (compound 25)

Summary for 7LHZ

• Entry DOI: 10.2210/pdb7lhz/pdb
• Descriptor: DNA topoisomerase 4 subunit B, DNA topoisomerase 4 subunit A chimera, DNA (5'-D(P*TP*AP*CP*GP*TP*TP*GP*TP*AP*T)-3'), DNA (5'-D(*GP*AP*TP*CP*AP*TP*AP*CP*AP*AP*CP*GP*TP*AP*A)-3'), ... (7 entities in total)
• Functional Keywords: gyrase, dna topoisomerase, parc, pare, isomerase-dna-inhibitor complex, isomerase/dna/inhibitor
• Biological source: Klebsiella pneumoniae 342; More
• Total number of polymer chains: 12
• Total formula weight: 370442.11

Authors

Noeske, J.,Shu, W.,Bellamacina, C. (deposition date: 2021-01-26, release date: 2021-05-12, Last modification date: 2023-10-18)

Primary citation

Lapointe, G.,Skepper, C.K.,Holder, L.M.,Armstrong, D.,Bellamacina, C.,Blais, J.,Bussiere, D.,Bian, J.,Cepura, C.,Chan, H.,Dean, C.R.,De Pascale, G.,Dhumale, B.,Fisher, L.M.,Fulsunder, M.,Kantariya, B.,Kim, J.,King, S.,Kossy, L.,Kulkarni, U.,Lakshman, J.,Leeds, J.A.,Ling, X.,Lvov, A.,Ma, S.,Malekar, S.,McKenney, D.,Mergo, W.,Metzger, L.,Mhaske, K.,Moser, H.E.,Mostafavi, M.,Namballa, S.,Noeske, J.,Osborne, C.,Patel, A.,Patel, D.,Patel, T.,Piechon, P.,Polyakov, V.,Prajapati, K.,Prosen, K.R.,Reck, F.,Richie, D.L.,Sanderson, M.R.,Satasia, S.,Savani, B.,Selvarajah, J.,Sethuraman, V.,Shu, W.,Tashiro, K.,Thompson, K.V.,Vaarla, K.,Vala, L.,Veselkov, D.A.,Vo, J.,Vora, B.,Wagner, T.,Wedel, L.,Williams, S.L.,Yendluri, S.,Yue, Q.,Yifru, A.,Zhang, Y.,Rivkin, A.
Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.
J.Med.Chem., 64:6329-6357, 2021

PubMed Abstract: Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound , which has potent activity against Gram-positive bacteria, a favorable safety profile, and excellent pharmacokinetic properties. Compound was found to be efficacious against fluoroquinolone-sensitive infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from , compound , and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of compared to fluoroquinolones.

PubMed: 33929852
DOI: 10.1021/acs.jmedchem.1c00375

Experimental method

X-RAY DIFFRACTION (3.3 Å)