Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex

Marie Glavier, Dhenesh Puvanendran, Dimitri Salvador, Marion Decossas, Gilles Phan, Cyril Garnier, Elisa Frezza, Quentin Cece, Guy Schoehn, Martin Picard, Jean-Christophe Taveau, Laetitia Daury, Isabelle Broutin () and Olivier Lambert ()
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Marie Glavier: University of Bordeaux
Dhenesh Puvanendran: Université de Paris
Dimitri Salvador: University of Bordeaux
Marion Decossas: University of Bordeaux
Gilles Phan: Université de Paris, CNRS
Cyril Garnier: Université de Paris, CNRS
Elisa Frezza: Université de Paris, CNRS
Quentin Cece: Université de Paris
Guy Schoehn: Université Grenoble Alpes, CNRS, CEA, Institute for Structural Biology (IBS)
Martin Picard: Université de Paris
Jean-Christophe Taveau: University of Bordeaux
Laetitia Daury: University of Bordeaux
Isabelle Broutin: Université de Paris, CNRS
Olivier Lambert: University of Bordeaux

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The tripartite multidrug efflux system MexAB-OprM is a major actor in Pseudomonas aeruginosa antibiotic resistance by exporting a large variety of antimicrobial compounds. Crystal structures of MexB and of its Escherichia coli homolog AcrB had revealed asymmetric trimers depicting a directional drug pathway by a conformational interconversion (from Loose and Tight binding pockets to Open gate (LTO) for drug exit). It remains unclear how MexB acquires its LTO form. Here by performing functional and cryo-EM structural investigations of MexB at various stages of the assembly process, we unveil that MexB inserted in lipid membrane is not set for active transport because it displays an inactive LTC form with a Closed exit gate. In the tripartite complex, OprM and MexA form a corset-like platform that converts MexB into the active form. Our findings shed new light on the resistance nodulation cell division (RND) cognate partners which act as allosteric factors eliciting the functional drug extrusion.

Date: 2020
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DOI: 10.1038/s41467-020-18770-5

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