01 Okt 2018
17:15 - 18:15
Biozentrum/Pharmazentrum, BZ 411, Klingelbergstrasse 50-70, Basel
Understanding structure and function of the promiscuous multidrug efflux system AcrAB-TolC
Vortrag von Prof. Dr. Klaas Martinus Pos, Institute of Biochemistry, Goethe University Frankfurt (DE)
In Gram-negative bacteria, tripartite efflux pumps, like AcrAB-TolC from Escherichia coli, play a prominent role in the resistance against multiple antibiotics. Transport of the drugs across the outer membrane and its coupling to the electrochemical gradient is dependent on the presence of all three protein components. The inner-membrane component AcrB is the substrate binding/transport and energy-coupling determinant of the entire three component complex. Functional analyses of the efflux activity of this pump revealed a daunting substrate polyspecificity. AcrB can recognize and transport a wide selection of toxic compounds including bile salts, organic solvents, detergents, dyes, and antibiotics from almost any class. With the help of X-ray crystallography and other biophysical/biochemical methods, our aim is to understand the molecular basis of this promiscuity. Regions deeply into the AcrB transporter core have been identified, which are involved in selection of drug substrates from non-substrates. Via directed evolution, AcrB variants with better-than-wildtype activities (for some antibiotic classes) have been selected and characterized. Structures of several AcrB variants in complex with drugs and an inhibitor of the pump reveal insight into the promiscuous binding phenotype.
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