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Dimethylaminophenyl hydrazides as inhibitors of the lipid transport protein LprG in mycobacteria.

07:00 EST 13th February 2020 | BioPortfolio

Summary of "Dimethylaminophenyl hydrazides as inhibitors of the lipid transport protein LprG in mycobacteria."

Assembly of the bacterial cell wall requires not only the biosynthesis of cell wall components, but also the transport of these metabolites to the cell exterior for assembly into polymers and membranes required for bacterial viability and virulence. LprG is a cell wall protein that is required for the virulence of Mycobacterium tuberculosis and is associated with lipid transport to the outer lipid layer or mycomembrane. Motivated by available co-crystal structures of LprG with lipids, we searched for potential inhibitors of LprG by performing a computational docking screen of ~250,000 commercially available small molecules. We identified several structurally related dimethylaminophenyl hydrazides that bind to LprG with moderate micromolar affinity and inhibit mycobacterial growth in a LprG-dependent manner. We found that mutation of F123 within the binding cavity of LprG conferred resistance to one of the most potent compounds. These findings provide evidence that the large hydrophobic substrate-binding pocket of LprG can be realistically and specifically targeted by small molecule inhibitors.

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This article was published in the following journal.

Name: ACS infectious diseases
ISSN: 2373-8227
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Medical and Biotech [MESH] Definitions

Protein components on the surface of LIPOPROTEINS. They form a layer surrounding the hydrophobic lipid core. There are several classes of apolipoproteins with each playing a different role in lipid transport and LIPID METABOLISM. These proteins are synthesized mainly in the LIVER and the INTESTINES.

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