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 cocrystal 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.