A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier

Significance The spread of multidrug-resistant infections demands antibiotic development. Although new antibiotics targeting gram-positive bacteria have been developed, it has been more than 50 y since a new class of antibiotics targeting gram-negative bacteria has been approved for clinical use. The strong outer membrane permeability barrier makes it difficult for compounds to reach intracellular targets, contributing greatly to the lack of new antibiotics targeting this class of microbes. Here, we describe a compound, MRL-494, that inhibits the assembly of proteins into the outer membrane by targeting an essential member of β-barrel assembly machine. This compound appears to act at the cell surface, avoiding both the outer membrane permeability barrier and the action of multidrug-resistance efflux pumps.