6P9M

Crystal structure of Mycobacterium tuberculosis KasA in complex with O6J

Summary for 6P9M

• Entry DOI: 10.2210/pdb6p9m/pdb
• Descriptor: 3-oxoacyl-[acyl-carrier-protein] synthase 1, SODIUM ION, N-(2-cyano-3-methyl-1H-indol-5-yl)pentane-1-sulfonamide, ... (6 entities in total)
• Functional Keywords: beta ketoacyl synthase i, lipid synthesis, fatty acid biosynthesis, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 43834.57

Authors

Capodagli, G.C.,Neiditch, M.B. (deposition date: 2019-06-10, release date: 2020-04-01, Last modification date: 2023-10-11)

Primary citation

Inoyama, D.,Awasthi, D.,Capodagli, G.C.,Tsotetsi, K.,Sukheja, P.,Zimmerman, M.,Li, S.G.,Jadhav, R.,Russo, R.,Wang, X.,Grady, C.,Richmann, T.,Shrestha, R.,Li, L.,Ahn, Y.M.,Ho Liang, H.P.,Mina, M.,Park, S.,Perlin, D.S.,Connell, N.,Dartois, V.,Alland, D.,Neiditch, M.B.,Kumar, P.,Freundlich, J.S.
A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.
Cell Chem Biol, 27:560-, 2020

PubMed Abstract: Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

PubMed: 32197094
DOI: 10.1016/j.chembiol.2020.02.007

Experimental method

X-RAY DIFFRACTION (2.256 Å)