BOYER, Esther; DESSOLIN, Jean; LUSTIG, Margaux; DECOSSAS, Marion; PHAN, Gilles; CECE, Quentin; DURAND, Gregory; DUBOIS, Veronique; SANSEN, Joris; TAVEAU, Jean-Christophe; BROUTIN, Isabelle; DAURY, Laetitia; LAMBERT, Olivier

doi:10.3390/antibiotics11020126

Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

DESSOLIN, Jean
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

LUSTIG, Margaux

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Article de revue

Ce document a été publié dans

Antibiotics. 2022-01-18, vol. 11, n° 2, p. 126

Résumé en anglais

Tripartite multidrug RND efflux systems made of an inner membrane transporter, an outer membrane factor (OMF) and a periplasmic adaptor protein (PAP) form a canal to expel drugs across Gram-negative cell wall. Structures of MexA–MexB–OprM and AcrA–AcrB–TolC, from Pseudomonas aeruginosa and Escherichia coli, respectively, depict a reduced interfacial contact between OMF and PAP, making unclear the comprehension of how OMF is recruited. Here, we show that a Q93R mutation of MexA located in the α-hairpin domain increases antibiotic resistance in the MexAQ93R–MexB–OprM-expressed strain. Electron microscopy single-particle analysis reveals that this mutation promotes the formation of tripartite complexes with OprM and non-cognate components OprN and TolC. Evidence indicates that MexAQ93R self-assembles into a hexameric form, likely due to interprotomer interactions between paired R93 and D113 amino acids. C-terminal deletion of OprM prevents the formation of tripartite complexes when mixed with MexA and MexB components but not when replacing MexA with MexAQ93R. This study reveals the Q93R MexA mutation and the OprM C-terminal peptide as molecular determinants modulating the assembly process efficacy with cognate and non-cognate OMFs, even though they are outside the interfacial contact. It provides insights into how OMF selectivity operates during the formation of the tripartite complex.< Réduire

Mots clés

Antibiotic resistance

Efflux pump

RND

URI

https://oskar-bordeaux.fr/handle/20.500.12278/202259

DOI

http://dx.doi.org/10.3390/antibiotics11020126

Project ANR

Biosenseurs originaux pour le criblage des ligands des Récepteurs Couplés aux Protéines G. Application au récepteur de la ghréline.

Unités de recherche

CBMN : Chimie & de Biologie des Membranes & des Nano-objets - UMR 5248

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Molecular Determinants for OMF Selectivity in Tripartite RND Multidrug Efflux Systems