Figure 7.

Inhibitors of MurJ. (a) Chemical structures of humimycins. The locations of resistance mutations mapped to the MurJ_TA structure are indicated as spheres. (b) Peptide sequence of Lys^M and resistance mutations to Lys^M mapped to the MurJ_TA structure. (c) Chemical structures of the putative small-molecule inhibitors DMPI, CDFI, Compound C, and Compound D. Resistance mutations to each were mapped to the MurJ_TA structure. (d) A barcode tabular summary of resistance mutations for each inhibitor and their locations on MurJ. Humimycins appeared to target the portal and cytoplasmic gate of MurJ, while Lys^M putatively targets the TM2–TM7 region of MurJ facing outside, toward the membrane. The mechanism of small-molecule inhibitors is less clear due to the small number of resistant mutants that have been isolated.

Abbreviations: CDFI, 2-(2-Chlorophenyl)-3-[1-(2,3-dimethylbenzyl)piperidin-4-yl]-5-fluoro-1H-indole; DMPI, 3-{1-[(2,3-Dimethylphenyl)methyl]piperidin-4-yl}-1-methyl-2-pyridin-4-yl-1H-indole; Lys^M, phage M lysis protein; MurJ_TA, Thermosipho africanus MurJ; TM, transmembrane helix.