Structure, Function and Regulation of Outer Membrane Proteins Involved in Drug Transport in Enterobactericeae: the OmpF/C - TolC Case

Overview

Journal Open Microbiol J

Publisher Bentham Open

Specialty Microbiology

Date 2013 Apr 10

PMID 23569467

Citations 33

Authors

Muriel Masi

Jean-Marie Pages

Affiliations

Soon will be listed here.

Abstract

Antibiotic translocation across membranes of Gram-negative bacteria is a key step for the activity on their specific intracellular targets. Resistant bacteria control their membrane permeability as a first line of defense to protect themselves against external toxic compounds such as antibiotics and biocides. On one hand, resistance to small hydrophilic antibiotics such as ß-lactams and fluoroquinolones frequently results from the « closing » of their way in: the general outer membrane porins. On the other hand, an effective way out for a wide range of antibiotics is provided by TolC-like proteins, which are outer membrane components of multidrug efflux pumps. Accordingly, altered membrane permeability, including porin modifications and/or efflux pumps' overexpression, is always associated to multidrug resistance (MDR) in a number of clinical isolates. Several recent studies have highlighted our current understanding of porins/TolC structures and functions in Enterobacteriaceae. Here, we review the transport of antibiotics through the OmpF/C general porins and the TolC-like channels with regards to recent data on their structure, function, assembly, regulation and contribution to bacterial resistance. Because MDR strains have evolved global strategies to identify and fight our antibiotic arsenal, it is important to constantly update our global knowledge on antibiotic transport.

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References

Gerken H, Misra R . Genetic evidence for functional interactions between TolC and AcrA proteins of a major antibiotic efflux pump of Escherichia coli. Mol Microbiol. 2004; 54(3):620-31. DOI: 10.1111/j.1365-2958.2004.04301.x. View

Hurdle J, ONeill A, Chopra I, Lee R . Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol. 2010; 9(1):62-75. PMC: 3496266. DOI: 10.1038/nrmicro2474. View

Kadzhaev K, Zingmark C, Golovliov I, Bolanowski M, Shen H, Conlan W . Identification of genes contributing to the virulence of Francisella tularensis SCHU S4 in a mouse intradermal infection model. PLoS One. 2009; 4(5):e5463. PMC: 2675058. DOI: 10.1371/journal.pone.0005463. View

Bolla J, Alibert-Franco S, Handzlik J, Chevalier J, Mahamoud A, Boyer G . Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative bacteria. FEBS Lett. 2011; 585(11):1682-90. DOI: 10.1016/j.febslet.2011.04.054. View

Koronakis V, Sharff A, Koronakis E, Luisi B, Hughes C . Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature. 2000; 405(6789):914-9. DOI: 10.1038/35016007. View

Akama H, Kanemaki M, Yoshimura M, Tsukihara T, Kashiwagi T, Yoneyama H . Crystal structure of the drug discharge outer membrane protein, OprM, of Pseudomonas aeruginosa: dual modes of membrane anchoring and occluded cavity end. J Biol Chem. 2004; 279(51):52816-9. DOI: 10.1074/jbc.C400445200. View

Nikaido E, Yamaguchi A, Nishino K . AcrAB multidrug efflux pump regulation in Salmonella enterica serovar Typhimurium by RamA in response to environmental signals. J Biol Chem. 2008; 283(35):24245-53. PMC: 2527123. DOI: 10.1074/jbc.M804544200. View

Lee H, Molla M, Cantor C, Collins J . Bacterial charity work leads to population-wide resistance. Nature. 2010; 467(7311):82-5. PMC: 2936489. DOI: 10.1038/nature09354. View

Hagan C, Kim S, Kahne D . Reconstitution of outer membrane protein assembly from purified components. Science. 2010; 328(5980):890-2. PMC: 2873164. DOI: 10.1126/science.1188919. View

10.

Srinivas N, Jetter P, Ueberbacher B, Werneburg M, Zerbe K, Steinmann J . Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science. 2010; 327(5968):1010-3. DOI: 10.1126/science.1182749. View

11.

Rolhion N, Carvalho F, Darfeuille-Michaud A . OmpC and the sigma(E) regulatory pathway are involved in adhesion and invasion of the Crohn's disease-associated Escherichia coli strain LF82. Mol Microbiol. 2007; 63(6):1684-700. DOI: 10.1111/j.1365-2958.2007.05638.x. View

12.

Demple B . Redox signaling and gene control in the Escherichia coli soxRS oxidative stress regulon--a review. Gene. 1996; 179(1):53-7. DOI: 10.1016/s0378-1119(96)00329-0. View

13.

Pages J, James C, Winterhalter M . The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol. 2008; 6(12):893-903. DOI: 10.1038/nrmicro1994. View

14.

Kim H, Xu Y, Lee M, Piao S, Sim S, Ha N . Functional relationships between the AcrA hairpin tip region and the TolC aperture tip region for the formation of the bacterial tripartite efflux pump AcrAB-TolC. J Bacteriol. 2010; 192(17):4498-503. PMC: 2937362. DOI: 10.1128/JB.00334-10. View

15.

Wu T, McCandlish A, Gronenberg L, Chng S, Silhavy T, Kahne D . Identification of a protein complex that assembles lipopolysaccharide in the outer membrane of Escherichia coli. Proc Natl Acad Sci U S A. 2006; 103(31):11754-9. PMC: 1544242. DOI: 10.1073/pnas.0604744103. View

16.

Buchanan S, Smith B, Venkatramani L, Xia D, Esser L, Palnitkar M . Crystal structure of the outer membrane active transporter FepA from Escherichia coli. Nat Struct Biol. 1999; 6(1):56-63. DOI: 10.1038/4931. View

17.

Piddock L . Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006; 19(2):382-402. PMC: 1471989. DOI: 10.1128/CMR.19.2.382-402.2006. View

18.

Nguyen T, Alegre E, Kelley S . Phylogenetic analysis of general bacterial porins: a phylogenomic case study. J Mol Microbiol Biotechnol. 2006; 11(6):291-301. DOI: 10.1159/000095631. View

19.

Andersen C, Hughes C, Koronakis V . Electrophysiological behavior of the TolC channel-tunnel in planar lipid bilayers. J Membr Biol. 2002; 185(1):83-92. DOI: 10.1007/s00232-001-0113-2. View

20.

Gerken H, Leiser O, Bennion D, Misra R . Involvement and necessity of the Cpx regulon in the event of aberrant beta-barrel outer membrane protein assembly. Mol Microbiol. 2010; 75(4):1033-46. PMC: 2927739. DOI: 10.1111/j.1365-2958.2009.07042.x. View