4PLB

Crystal Structure of S.A. gyrase-AM8191 complex

Summary for 4PLB

• Entry DOI: 10.2210/pdb4plb/pdb
• Descriptor: DNA (5'-D(P*AP*GP*CP*CP*GP*TP*AP*GP*GP*GP*CP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), Chimera protein of DNA gyrase subunits B and A, 6-[({(1r,4S)-1-[(1S)-2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)-1-hydroxyethyl]-2-oxabicyclo[2.2.2]oct-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, ... (6 entities in total)
• Functional Keywords: gyase inhibitor complex, isomerase-isomerase inhibitor-dna complex, isomerase/isomerase inhibitor/dna
• Biological source: Staphylococcus aureus; More
• Cellular location: Cytoplasm : P20831
• Total number of polymer chains: 4
• Total formula weight: 169329.35

Authors

Lu, J.,Patel, S.,Soisson, S. (deposition date: 2014-05-16, release date: 2014-06-18, Last modification date: 2023-12-27)

Primary citation

Singh, S.B.,Kaelin, D.E.,Wu, J.,Miesel, L.,Tan, C.M.,Meinke, P.T.,Olsen, D.,Lagrutta, A.,Bradley, P.,Lu, J.,Patel, S.,Rickert, K.W.,Smith, R.F.,Soisson, S.,Wei, C.,Fukuda, H.,Kishii, R.,Takei, M.,Fukuda, Y.
Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents.
Acs Med.Chem.Lett., 5:609-614, 2014

PubMed Abstract: Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

PubMed: 24900889
DOI: 10.1021/ml500069w

Experimental method

X-RAY DIFFRACTION (2.69 Å)