Trinity revealed: Stoichiometric complex assembly of a bacterial multidrug efflux pump

Abstract

The capacity of bacteria to expel from themselves a broad diversity of compounds confers upon them resistance to drugs and other bacteriocidal agents (1). In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa multidrug efflux is achieved by energy-powered macromolecular machinery that extrudes cytotoxic substances like multiple anti biotics, dyes, bile salts, and detergents from the inner membrane of the cell directly into the medium, bypassing the periplasm and the outer membrane. Known complexes of such multidrug efflux pumps are composed for three types of components: an outer membrane channel, a periplasmic bridge, and an inner membrane energy-transducer. There are a variety of possible inner membrane components, which can include members of the ATP binding cassette transporter superfamily, the major facilitator superfamily, or the resistance nodulation cell division (RND) superfamily. These inner membrane-located units are the major sites for substrate recognition and energy transduction of the entire tripartite system and function in conjunction with the 2 other pump components. The periplasmic bridge component often goes by the name of “membrane fusion protein” (MFP) for historical reasons and is represented by the AcrA protein. Well-characterized representatives of the outer membrane factor (OMF) are channel-like proteins such as TolC. Both the outer membrane and tripartite efflux pumps are considered to be the main barrier for drugs on their way to the inside of the bacterial cell (2). Importantly, only assembly of all 3 components into a trinity results in an active and effective drug efflux phenotype. In this issue of PNAS, Symmons et al. (3) complete the picture of an E. coli 3-component multidrug efflux system with a well-tested and insightful model.