Molecular analysis of efflux pump-based antibiotic resistance

Multidrug efflux transporters are normal constituents of bacterial cells. These transporters are major contributors to intrinsic resistance of bacteria to many anti-microbial agents. In clinical settings, exposure to antibiotics promotes the mutational overexpression of active or silent multidrug transporters, leading to increased antibiotic resistance without acquisition of multiple, specific resistance determinants. The paradoxical ability of multidrug transporters to recognize and efficiently expel from cells scores of dissimilar organic compounds has been in the focus of extensive research for many years. Several independent studies implied that the mechanistic basis of such ability lies in a distinctive locus of the transporter-substrate interaction: the multidrug transporters select and bind their substrates within the phospholipid bilayer. The recently reported high-resolution structure of a complete MsbA transporter of Escherichia coli provides a solid structural basis for these studies. Although the majority of multidrug transporters function as single-component pumps, major transporters of Gram-negative bacteria are organized as three-component structures. Special outer membrane channels and periplasmic proteins belonging to the membrane fusion protein family enable drug efflux across a Gram-negative two-membrane envelope, directly into the external medium. This minireview focuses on the current status of research in the field of multidrug efflux mechanisms.