Crystal Structure of the Multidrug Exporter MexB from Pseudomonas aeruginosa

Sennhauser, Gaby; Bukowska, M.A.; Briand, Christophe; Grütter, Markus G.

doi:10.1016/j.jmb.2009.04.001

Cited by 205 publications

(229 citation statements)

References 33 publications

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“…In some instances, the nonsense mutations may well have had clinical or physiological significance. For example, mexB, which encodes a component of the principal broadspectrum multidrug efflux pump in P. aeruginosa, carried a nonsense mutation that truncated the encoded protein in both isolates from patient 5 at residue Y891, leading to loss of the last four transmembrane helices, one of which is known to be essential for pump function (32). In both isolates from patient 6, the protein encoded by the quorum-sensing master regulator, lasR (25,34,42), was truncated at residue E124 within the OdDHL-binding domain.…”

Section: Resultsmentioning

confidence: 99%

Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients

et al. 2012

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ABSTRACTThe airways of individuals with cystic fibrosis (CF) often become chronically infected with unique strains of the opportunistic pathogenPseudomonas aeruginosa. Several lines of evidence suggest that the infectingP. aeruginosalineage diversifies in the CF lung niche, yet so far this contemporary diversity has not been investigated at a genomic level. In this work, we sequenced the genomes of pairs of randomly selected contemporary isolates sampled from the expectorated sputum of three chronically infected adult CF patients. Each patient was infected by a distinct strain ofP. aeruginosa. Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) were identified in the DNA common to the paired isolates from different patients. The paired isolates from one patient differed due to just 1 SNP and 8 indels. The paired isolates from a second patient differed due to 54 SNPs and 38 indels. The pair of isolates from the third patient both contained amutSmutation, which conferred a hypermutator phenotype; these isolates cumulatively differed due to 344 SNPs and 93 indels. In two of the pairs of isolates, a different accessory genome composition, specifically integrated prophage, was identified in one but not the other isolate of each pair. We conclude that contemporary isolates from a single sputum sample can differ at the SNP, indel, and accessory genome levels and that the cross-sectional genomic variation among coeval pairs ofP. aeruginosaCF isolates can be comparable to the variation previously reported to differentiate between paired longitudinally sampled isolates.

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Section: Resultsmentioning

confidence: 99%

Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients

et al. 2012

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“…This concept of conformational cycling or functional rotation was then substantiated by the finding that disulfide cross-linking of nearby residues, although apparently occurring in only one or two protomers, nearly completely inactivated the trimeric complex (73). (The AcrB homolog MexB of P. aeruginosa has been crystallized without [74] and with [75] an added inhibitor, a pyridopyrimidine derivative.) In a similar vein, when the AcrB trimer was produced as a covalently linked single protein, and only one protomeric unit was inactivated in the proton translocation pathway, the entire trimeric complex became inactive (76).…”

Section: Figmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…Of the 11 RND efflux pumps identified in this organism, 10 pumps, MexAB-OprM (Poole et al, 1993), MexCD-OprJ (Poole et al, 1996), MexEF-OprN (Kohler et al, 1997), MexGHI-OpmD (Aendekerk et al, 2002;Sekiya et al, 2003), MexJK (Chuanchuen et al, 2002), MexMN (Mima et al, 2005), MexPQ-OpmE (Mima et al, 2005), MexVW (Li et al, 2003), MexXY (Mine et al, 1999;Westbrock-Wadman et al, 1999) and TriABCOpmH (Mima et al, 2007), have been experimentally confirmed, and their properties have been reported. The RND-type efflux pump usually consists of three components to fulfil the function properly and includes an innermembrane component (RND component), a periplasmic component (MFP component), and an outer-membrane component (OMP component) (Touze et al, 2004), and the three-dimensional structures of MexA, MexB and OprM have been reported (Akama et al, 2004a, b;Higgins et al, 2004;Sennhauser et al, 2009). However, regarding the most recently analysed RND efflux pump in P. aeruginosa, TriABC-OpmH, it has been reported that this system needs four components: an RND component, two MFP components and an OMP component (Mima et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND components in Pseudomonas aeruginosa

Mima

Kohira

et al. 2009

Microbiology

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muxA-muxB-muxC-opmB (formerly PA2528-PA2527-PA2526-opmB), encoding a putative resistance nodulation cell division (RND)-type multidrug efflux pump system, was cloned from Pseudomonas aeruginosa PAO1. Introduction of muxABC-opmB into P. aeruginosa YM64, a drug-hypersusceptible strain, led to elevated MICs of aztreonam, macrolides, novobiocin and tetracycline. Since muxB and muxC, both of which encode RND components, were essential for function, MuxABC-OpmB is thought to be a drug efflux pump with four components. One novobiocin-resistant mutant, PMX725, isolated from P. aeruginosa PMX7 showed elevated resistance not only to novobiocin but also to aztreonam, macrolides and tetracycline. Increased mRNA expression of muxABC-opmB was observed in the mutant PMX725 compared with the parental strain. Sequencing analysis revealed that a single-nucleotide insertion had occurred in the deduced promoter region for muxABC-opmB in PMX725. In this study, we have characterized the last RND-type multidrug efflux pump predicted from the genome sequence in P. aeruginosa.

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Crystal Structure of the Multidrug Exporter MexB from Pseudomonas aeruginosa

Cited by 205 publications

References 33 publications

Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients

Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND components in Pseudomonas aeruginosa

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