7MVS

DNA gyrase complexed with uncleaved DNA and Compound 7 to 2.6A resolution

Summary for 7MVS

• Entry DOI: 10.2210/pdb7mvs/pdb
• Descriptor: DNA gyrase subunit B,DNA gyrase subunit A, 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'), CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, dna, gyrase, antibiotic, isomerase-dna-antibiotic complex, isomerase/dna/antibiotic
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 4
• Total formula weight: 169386.81

Authors

Ratigan, S.C.,McElroy, C.A. (deposition date: 2021-05-15, release date: 2021-10-20, Last modification date: 2023-10-18)

Primary citation

Lu, Y.,Vibhute, S.,Li, L.,Okumu, A.,Ratigan, S.C.,Nolan, S.,Papa, J.L.,Mann, C.A.,English, A.,Chen, A.,Seffernick, J.T.,Koci, B.,Duncan, L.R.,Roth, B.,Cummings, J.E.,Slayden, R.A.,Lindert, S.,McElroy, C.A.,Wozniak, D.J.,Yalowich, J.,Mitton-Fry, M.J.
Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA.
J.Med.Chem., 64:15214-15249, 2021

PubMed Abstract: Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound . This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable cardiovascular safety profile, and efficacy in a murine model of methicillin-resistant infection.

PubMed: 34614347
DOI: 10.1021/acs.jmedchem.1c01250

Experimental method

X-RAY DIFFRACTION (2.60137142659 Å)