Molecular Determinants for OMF Selectivity in Tripartite RND Multidrug Efflux Systems.

Autor:	Boyer E; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Dessolin J; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Lustig M; Laboratoire CiTCoM, CNRS, Université de Paris, 75006 Paris, France., Decossas M; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Phan G; Laboratoire CiTCoM, CNRS, Université de Paris, 75006 Paris, France., Cece Q; Laboratoire CiTCoM, CNRS, Université de Paris, 75006 Paris, France., Durand G; Unité Propre de Recherche et d'Innovation, Université d'Avignon, Equipe S2CB, 84916 Avignon, France., Dubois V; MFP, UMR 5234, CNRS, Univiversité de Bordeaux, 33000 Bordeaux, France., Sansen J; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Taveau JC; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Broutin I; Laboratoire CiTCoM, CNRS, Université de Paris, 75006 Paris, France., Daury L; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France., Lambert O; CBMN UMR 5248, Bordeaux INP, CNRS, Université de Bordeaux, 33600 Pessac, France.
Jazyk:	angličtina
Zdroj:	Antibiotics (Basel, Switzerland) [Antibiotics (Basel)] 2022 Jan 18; Vol. 11 (2). Date of Electronic Publication: 2022 Jan 18.
DOI:	10.3390/antibiotics11020126
Abstrakt:	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 MexA Q93R -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 MexA Q93R 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 MexA Q93R . 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.
Databáze:	MEDLINE
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