Docking simulation and antibiotic discovery targeting the MlaC protein in Gram‐negative bacteria

To maintain the lipid asymmetry of the cell envelope in Gram‐negative bacteria, the MlaC protein serves as a lipid transfer factor and delivers phospholipids from the outer to the inner membrane. A strategy of antibiotic discovery is to design a proper compound that can tightly bind to the MlaC protein and inhibit the MlaC function. In this study, we performed virtual screening on multiple MlaC structures obtained from molecular dynamics simulations to identify potential MlaC binders. Our results suggested that clorobiocin is a compound that could bind to the MlaC protein. Through the comparison of the bound geometry between clorobiocin and novobiocin, we pointed out that the methyl‐pyrrole group of the noviose sugar in clorobiocin forms hydrophobic interactions with amino acids in the phospholipid binding pocket, which allows the compound to bind deep in the active site. This also explains why clorobiocin shows a tighter binding affinity than novobiocin. Our study highlights a practical path of antibiotic development against Gram‐negative bacteria.