The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs

Paulsen, Ian T.; Skurray, Ronald A.; Tam, Roland; Saier, Milton H.; Turner, Raymond J.; Weiner, Joël H.; Goldberg, Edward B.; Grinius, L.

doi:10.1111/j.1365-2958.1996.tb02462.x

Cited by 268 publications

(246 citation statements)

References 69 publications

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“…Bacteria possess other types of transporters that use the energy from proton or electrochemical gradients to pump chemicals or ions cross the cytoplasmic membrane (37,38,53). For instance, the small multidrug resistance transporters are typically 105-121 amino acids long, contain four predicted trans-membrane helices, and function as homo-or heterooligomers (37,38,53,54).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the small multidrug resistance transporters are typically 105-121 amino acids long, contain four predicted trans-membrane helices, and function as homo-or heterooligomers (37,38,53,54). Examples include heterodimeric complexes, such as EbrA/EbrB of Bacillus subtilis (39), as well as the homodimeric transporter EmrE of E. coli (54).…”

Section: Discussionmentioning

confidence: 99%

“…2B) (16), which display distant sequence similarity to the multidrug efflux pump exporter EmrE (37)(38)(39). In-frame chromosomal deletion mutants of pmrL and pmrM, generated in a polymyxin-resistant pmrA c parental strain, regain polymyxin sensitivity.…”

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confidence: 99%

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An Undecaprenyl Phosphate-Aminoarabinose Flippase Required for Polymyxin Resistance in Escherichia coli

Yan¹,

Guan²,

Raetz

2007

Journal of Biological Chemistry

135

136

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Modification of lipid A with the 4-amino-4-deoxy-L-arabinose (L-Ara4N) moiety is required for resistance to polymyxin and cationic antimicrobial peptides in Escherichia coli and Salmonella typhimurium. An operon of seven genes (designated pmrHFIJKLM in S. typhimurium), which is regulated by the PmrA transcription factor and is also present in E. coli, is necessary for the maintenance of polymyxin resistance. We previously elucidated the roles of pmrHFIJK in the biosynthesis and attachment of L-Ara4N to lipid A and renamed these genes arn-BCADT, respectively. We now propose functions for the last two genes of the operon, pmrL and pmrM. Chromosomal inactivation of each of these genes in an E. coli pmrA c parent switched its phenotype from polymyxin-resistant to polymyxin-sensitive. The lipid A moiety of lipopolysaccharide (LPS) 4 in the outer membranes of Gram-negative bacteria typically consists of a ␤,1Ј-6-linked disaccharide of glucosamine, modified with phosphate groups at the 1-and 4Ј-positions, and with R-3-hydroxyacyl chains at the 2-, 3-, 2Ј-, and 3Ј-positions (Fig.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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An Undecaprenyl Phosphate-Aminoarabinose Flippase Required for Polymyxin Resistance in Escherichia coli

Yan¹,

Guan²,

Raetz

2007

Journal of Biological Chemistry

135

136

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“…In addition, 2 of the aforementioned transporters have been thoroughly characterized. MdfA, a major facilitator superfamily (MFS) transporter that functions as a single 12 TM polypeptide, and EmrE, a small multidrug resistance (SMR) family transporter that functions as a homodimer, remove toxic compounds, including acriflavine and ethidium, from the cytoplasm in exchange for protons (11)(12)(13)(14)(15)(16)(17).…”

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confidence: 99%

A coordinated network of transporters with overlapping specificities provides a robust survival strategy

Nir

Schuldiner

2009

Proc. Natl. Acad. Sci. U.S.A.

176

180

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Multidrug transporters provide a survival strategy for living organisms. As expected given their central role in survival, these transporters are ubiquitous, and in many genomes, several genes coding for putative transporters have been identified. However, in an organism such as Escherichia coli mutations in genes coding for transporters other than the major AcrAB-TolC multidrug efflux transporter have only a marginal effect on phenotype. Thus, whether the physiological role of the transporters identified is indeed drug export has been questioned. We show here that the minor effect of single mutations is due to the overlapping functionality of several transporters. This was revealed by generating multiple chromosomal deletion mutations in genes coding for transporters that share the same substrate and testing their effect on the resistance phenotype. In addition, complementation studies imply that AcrAB-TolC confers robust resistance provided that single-component transporters in the plasma membrane are functional. This finding supports the contention that hydrophobic drugs are removed in a 2-stage process: AcrAB-TolC removes substrates from the periplasmic space, while single-component transporters remove them from the cell. The overlapping specificities of the transporters ensure coverage of a wide range of xenobiotics and provide robustness in the response to environmental stress. This strategy also confers evolvability to the organism by reducing constraints on change and allowing the accumulation of nonlethal variation.AcrAB ͉ drug resistance ͉ EmrE ͉ MdfA ͉ multidrug transporters

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“…PMF-dependent multidrug efflux proteins have been classified into three distinct families of membrane transport proteins based on comparative sequence analysis: the major facilitator superfamily (4 -6), e.g. Bmr from Bacillus subtilis (7) and QacA from Staphylococcus aureus (8,9); the small multidrug resistance family (10), e.g. EmrE from Escherichia coli (11) and Smr from S. aureus (12,13); and the resistance/nodulation/cell division family (14), e.g.…”

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confidence: 99%

Bioenergetics of the Staphylococcal Multidrug Export Protein QacA

Mitchell¹,

Paulsen²,

Brown

et al. 1999

Journal of Biological Chemistry

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The multidrug efflux pump QacA from Staphylococcus aureus confers resistance to an extensive range of structurally dissimilar compounds. Fluorimetric analyses demonstrated that QacA confers resistance to the divalent cation 4,6-diamidino-2-phenylindole, utilizing a proton motive force-dependent efflux mechanism previously demonstrated for QacA-mediated resistance to the monovalent cation ethidium. Both the ionophores nigericin and valinomycin inhibited QacA-mediated export of ethidium, indicating an electrogenic drug/nH ؉ (n > 2) antiport mechanism. The kinetic parameters, K m and V max , were determined for QacA-mediated export of four fluorescent substrates, 4,6-diamidino-2-phenylindole, 3,3-dipropyloxacarbocyanine, ethidium, and pyronin Y. Competition studies showed that QacA-mediated ethidium export is competitively inhibited by monovalent cations, e.g. benzalkonium, and non-competitively inhibited by divalent cations, e.g. propamidine, which suggests that monovalent and divalent cations bind at distinct sites on the QacA protein. The quaternary ammonium salt, 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene, was used as a membrane-specific fluorescence probe and demonstrated that the amount of substrate entering the inner leaflet was significantly reduced in QacA-containing strains, supporting the notion that the substrate is extruded directly from the membrane.

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The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs

Cited by 268 publications

References 69 publications

An Undecaprenyl Phosphate-Aminoarabinose Flippase Required for Polymyxin Resistance in Escherichia coli

An Undecaprenyl Phosphate-Aminoarabinose Flippase Required for Polymyxin Resistance in Escherichia coli

A coordinated network of transporters with overlapping specificities provides a robust survival strategy

Bioenergetics of the Staphylococcal Multidrug Export Protein QacA

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