1,183
Views
59
CrossRef citations to date
0
Altmetric
Reviews

Understanding efflux in Gram-negative bacteria: opportunities for drug discovery

, PhD
Pages 633-642 | Published online: 19 May 2012

Bibliography

  • Walsh C. Antibiotic Resistance. American Society for Microbiology Press; Washington, D.C: 2003
  • Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev 2011;24(1):71-109
  • Lewis K. Multidrug tolerance of biofilms and persister cells. Curr Top Microbiol Immunol 2008;322:107-31
  • Davies JC, Bilton D. Bugs, biofilms, and resistance in cystic fibrosis. Respir Care 2009;54(5):628-40
  • Hoiby N, Bjarnsholt T, Givskov M, Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010;35(4):322-32
  • Haussler S, Rohde M, Steinmetz I. Highly resistant Burkholderia pseudomallei small colony variants isolated in vitro and in experimental melioidosis. Med Microbiol Immunol 1999;188:91-7
  • Fetar H, Gilmour C, Klinoski R, mexEF-oprN multidrug efflux operon of Pseudomonas aeruginosa: regulation by the MexT activator in response to nitrosative stress and chloramphenicol. Antimicrob Agents Chemother 2011;55(2):508-14
  • Fraud S, Poole K. Oxidative stress induction of the MexXY multidrug efflux genes and promotion of aminoglycoside resistance development in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2011;55(3):1068-74
  • Poole K. Pseudomonas aeruginosa: resistance to the max. Front Microbiol 2011;2:65
  • Piddock LJ. Multidrug-resistance efflux pumps - not just for resistance. Nat Rev Microbiol 2006;4:629-36
  • Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 2006;19:382-402
  • Lomovskaya O, Zgurskaya HI, Totrov M, Watkins WJ. Waltzing transporters and 'the dance macabre' between humans and bacteria. Nat Rev Drug Discov 2007;6(1):56-65
  • Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update. Drugs 2009;69(12):1555-623
  • Nikaido H, Pages JM. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol Rev 2012;36(2):340-63
  • Balganesh M, Dinesh N, Sharma S, Efflux Pumps of Mycobacterium tuberculosis play a significant role in anti-tuberculosis activity of potential drug candidates. Antimicrob Agents Chemother 2012;56(5):2643-51
  • Li X, Zolli-Juran M, Cechetto JD, Multicopy suppressors for novel antibacterial compounds reveal targets and drug efflux susceptibility. Chem Biol 2004;11(10):1423-30
  • Caughlan RE, Jones AK, Delucia AM, Mechanisms decreasing in vitro susceptibility to the LpxC inhibitor CHIR-090 in the gram-negative pathogen Pseudomonas aeruginosa. Antimicrob Agents Chemother 2012;56(1):17-27
  • Poole K. Uninhibited antibiotic target discovery via chemical genetics. Nat Biotechnol 2004;22:1528-9
  • Pages JM, James CE, Winterhalter M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 2008;6(12):893-903
  • Hancock REW. Resistance mechanisms in Pseudomonas aeruginosa and other non-fermentative bacteria. Clin Infect Dis 1998;27(Suppl 1):S93-9
  • Raetz CRH, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem 2002;71:635-700
  • Raetz CR, Reynolds CM, Trent MS, Bishop RE. Lipid A modification systems in gram-negative bacteria. Annu Rev Biochem 2007;76:295-329
  • Sampson BA, Misra R, Benson SA. Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability. Genetics 1989;122(3):491-501
  • Silhavy TJ, Kahne D, Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol 2010;2(5):a000414
  • Novem V, Shui G, Wang D, Structural and biological diversity of lipopolysaccharides from Burkholderia pseudomallei and Burkholderia thailandensis. Clin Vaccine Immunol 2009;16(10):1420-8
  • Hancock RE. Aminoglycoside uptake and mode of action-with special reference to streptomycin and gentamicin. I. Antagonists and mutants. J Antimicrob Chemother 1981;8(4):249-76
  • Godfrey AJ, Shahrabadi MS, Bryan LE. Distribution of porin and lipopolysaccharide antigens on a Pseudomonas aeruginosa permeability mutant. Antimicrob Agents Chemother 1986;30(5):802-5
  • Clements JM, Coignard F, Johnson I, Antibacterial activities and characterization of novel inhibitors of LpxC. Antimicrob Agents Chemother 2002;46(6):1793-9
  • Kline T, Andersen NH, Harwood EA, Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC. J Med Chem 2002;45(14):3112-29
  • Mdluli KE, Witte PR, Kline T, Molecular validation of LpxC as an antibacterial drug target in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006;50(6):2178-84
  • Barb AW, Zhou P. Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol 2008;9(1):9-15
  • Langsdorf EF, Malikzay A, Lamarr WA, Screening for antibacterial inhibitors of the UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) using a high-throughput mass spectrometry assay. J Biomol Screen 2010;15(1):52-61
  • Lee CJ, Liang X, Chen X, Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design. Chem Biol 2011;18(1):38-47
  • Brown MF, Reilly U, Abramite JA, Potent inhibitors of LpxC for the treatment of gram-negative infections. J Med Chem 2012;55(2):914-23
  • Srinivas N, Jetter P, Ueberbacher BJ, Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 2010;327(5968):1010-13
  • Kumar A, Schweizer HP. Bacterial resistance to antibiotics: active efflux and reduced uptake. Adv Drug Deliv Rev 2005;57:1486-513
  • Tal N, Schuldiner S. A coordinated network of transporters with overlapping specificities provides a robust survival strategy. Proc Natl Acad Sci USA 2009;106(22):9051-6
  • Cloeckaert A, Baucheron S, Chaslus-Dancla E. Nonenzymatic chloramphenicol resistance mediated by IncC plasmid R55 is encoded by a floR gene variant. Antimicrob Agents Chemother 2001;45(8):2381-2
  • Poole K, Srikumar R. Multidrug efflux in Pseudomonas aeruginosa: components, mechanisms and clinical significance. Curr Topics Med Chem 2001;1:59-71
  • Chopra I. New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors. Drug Resist Updat 2002;5(3-4):119-25
  • Butaye P, Cloeckaert A, Schwarz S. Mobile genes coding for efflux-mediated antimicrobial resistance in Gram-positive and Gram-negative bacteria. Int J Antimicrob Agents 2003;22:205-10
  • Schwarz S, Kehrenberg C, Doublet B, Cloeckaert A. Molecular basis of bacterial resistance to chloramphenicol and florfenicol. FEMS Microbiol Rev 2004;28(5):519-42
  • Hooper DC. Efflux pumps and nosocomial antibiotic resistance: a primer for hospital epidemiologists. Clin Infect Dis 2005;40(12):1811-17
  • Rothstein DM, McGlynn M, Bernan V, Detection of tetracyclines and efflux pump inhibitors. Antimicrob Agents Chemother 1993;37(8):1624-9
  • Levy SB. The challenge of antibiotic resistance. Sci Am 1998;278(3):46-53
  • Nelson ML, Levy SB. Reversal of tetracycline resistance mediated by different bacterial tetracycline resistance determinants by an inhibitor of the Tet(B) antiport protein. Antimicrob Agents Chemother 1999;43:1719-24
  • Nelson ML. Attacking the superbugs. Drug Disc World 2002;Spring:77-82
  • Lee A, Mao W, Warren MS, Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 2000;182:3142-50
  • Lomovskaya O, Watkins W. Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J Mol Microbiol Biotechnol 2001;3:225-36
  • Poole K. Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 2005;56:20-51
  • Deininger KN, Horikawa A, Kitko RD, A requirement of TolC and MDR efflux pumps for acid adaptation and GadAB induction in Escherichia coli. PLoS One 2011;6(4):e18960
  • Kvist M, Hancock V, Klemm P. Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl Environ Microbiol 2008;74(23):7376-82
  • Hirakata Y, Kondo A, Hoshino K, Efflux pump inhibitors reduce the invasiveness of Pseudomonas aeruginosa. Int J Antimicrob Agents 2009;34(4):343-6
  • Ferhat M, Atlan D, Vianney A, The TolC protein of Legionella pneumophila plays a major role in multi-drug resistance and the early steps of host invasion. PLoS One 2009;4(11):e7732
  • Buckley AM, Webber MA, Cooles S, The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis. Cell Microbiol 2006;8(5):847-56
  • Gil H, Platz GJ, Forestal CA, Deletion of TolC orthologs in Francisella tularensis identifies roles in multidrug resistance and virulence. Proc Natl Acad Sci USA 2006;103(34):12897-902
  • Reddy JD, Reddy SL, Hopkins DL, Gabriel DW. TolC is required for pathogenicity of Xylella fastidiosa in Vitis vinifera grapevines. Mol Plant Microbe Interact 2007;20(4):403-10
  • Koronakis V, Sharff A, Koronakis E, Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 2000;405:914-19
  • Murakami S, Nakashima R, Yamashita E, Yamaguchi A. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 2002;419:587-93
  • Yu EW, McDermott G, Zgurskaya HI, Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 2003;300(5621):976-80
  • Akama H, Matsuura T, Kashiwagi S, Crystal structure of the membrane fusion protein, MexA, of the multidrug transporter in Pseudomonas aeruginosa. J Biol Chem 2004;279(25):25939-42
  • Lambert O, Benabdelhak H, Chami M, Trimeric structure of OprN and OprM efflux proteins from Pseudomonas aeruginosa, by 2D electron crystallography. J Struct Biol 2005;150(1):50-7
  • Murakami S, Nakashima R, Yamashita E, Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 2006;443(7108):173-9
  • Seeger MA, Schiefner A, Eicher T, Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 2006;313(5791):1295-8
  • Sennhauser G, Amstutz P, Briand C, Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol 2007;5(1):e7
  • Sennhauser G, Bukowska MA, Briand C, Grutter MG. Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J Mol Biol 2009;389(1):134-45
  • Lynch AS. Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view. Biochem Pharmacol 2006;71(7):949-56
  • Mahamoud A, Chevalier J, Alibert-Franco S, Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 2007;59(6):1223-9
  • Stavri M, Piddock LJ, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 2007;59(6):1247-60
  • Vergidis PI, Falagas ME. Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options. Curr Opin Investig Drugs 2008;9(2):176-83
  • Martins M, Dastidar SG, Fanning S, Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: mechanisms for their direct and indirect activities. Int J Antimicrob Agents 2008;31(3):198-208
  • Kamicker BJ, Sweeney MT, Kaczmarek F, Bacterial efflux pump inhibitors. Methods Mol Med 2008;142:187-204
  • Vila J, Martinez JL. Clinical impact of the over-expression of efflux pump in nonfermentative Gram-negative bacilli, development of efflux pump inhibitors. Curr Drug Targets 2008;9(9):797-807
  • Zechini B, Versace I. Inhibitors of multidrug resistant efflux systems in bacteria. Recent Patents Anti Infect Drug Discov 2009;4(1):37-50
  • Piddock LJ, Garvey MI, Rahman MM, Gibbons S. Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother 2010;65(6):1215-23
  • Tegos GP, Haynes M, Strouse JJ, Microbial efflux pump inhibition: tactics and strategies. Curr Pharm Des 2011;17(13):1291-302
  • Pages JM, Amaral L, Fanning S. An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat gram-negative resistant bacteria. Curr Med Chem 2011;18(19):2969-80
  • Lomovskaya O, Warren MS, Lee A, Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 2001;45:105-16
  • Matsumoto Y, Hayama K, Sakakihara S, Evaluation of multidrug efflux pump inhibitors by a new method using microfluidic channels. PLoS One 2011;6(4):e18547
  • Renau TE, Leger R, Flamme EM, Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 1999;42:4928-31
  • Hasdemir UO, Chevalier J, Nordmann P, Pages JM. Detection and prevalence of active drug efflux mechanism in various multidrug-resistant Klebsiella pneumoniae strains from Turkey. J Clin Microbiol 2004;42(6):2701-6
  • Mazzariol A, Tokue Y, Kanegawa TM, High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrob Agents Chemother 2000;44(12):3441-3
  • Baucheron S, Imberechts H, Chaslus-Dancla E, Cloeckaert A. The AcrB multidrug transporter plays a major role in high-level fluoroquinolone resistance in Salmonella enterica serovar typhimurium phage type DT204. Microb Drug Resist 2002;8(4):281-9
  • Mallea M, Chevalier J, Eyraud A, Pages JM. Inhibitors of antibiotic efflux pump in resistant Enterobacter aerogenes strains. Biochem Biophys Res Commun 2002;293(5):1370-3
  • Mamelli L, Amoros JP, Pages JM, Bolla JM. A phenylalanine-arginine beta-naphthylamide sensitive multidrug efflux pump involved in intrinsic and acquired resistance of Campylobacter to macrolides. Int J Antimicrob Agents 2003;22:237-41
  • Cortez-Cordova J, Kumar A. Activity of the efflux pump inhibitor phenylalanine-arginine beta-naphthylamide against the AdeFGH pump of Acinetobacter baumannii. Int J Antimicrob Agents 2011;37(5):420-4
  • Yoshida K, Nakayama K, Ohtsuka M, MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem 2007;15(22):7087-97
  • Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic–a vision for applied use. Biochem Pharmacol 2006;71(7):910-18
  • Zeng B, Wang H, Zou L, Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump. Biosci Biotechnol Biochem 2010;74(11):2237-41
  • Mahamoud A, Chevalier J, Baitiche M, An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates. Microbiology 2011;157(Pt 2):566-71
  • Coban AY, Guney AK, Tanriverdi Cayci Y, Durupinar B. Effect of 1-(1-Naphtylmethyl)-piperazine, an efflux pump inhibitor, on antimicrobial drug susceptibilities of clinical Acinetobacter baumannii isolates. Curr Microbiol 2011;62(2):508-11
  • Liu YS, Zhang YQ, Yang LX, Gene-specific silencing induced by parallel complementary RNA in Pseudomonas aeruginosa. Biotechnol Lett 2009;31(10):1571-5
  • Meng J, Bai H, Jia M, Restoration of antibiotic susceptibility in fluoroquinolone-resistant Escherichia coli by targeting acrB with antisense phosphorothioate oligonucleotide encapsulated in novel anion liposome. J Antibiot (Tokyo) 2011;65:129-34
  • Al-Hamad A, Burnie J, Upton M. Enhancement of antibiotic susceptibility of Stenotrophomonas maltophilia using a polyclonal antibody developed against an ABC multidrug efflux pump. Can J Microbiol 2011;57(10):820-8
  • Takatsuka Y, Chen C, Nikaido H. Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci USA 2010;107(15):6559-65
  • Lomovskaya O, Lee A, Hoshino K, Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1999;43(6):1340-6
  • Kumar A, Chua K-L, Schweizer HP. Method for regulated expression of single-copy efflux pump genes in a surrogate Pseudomonas aeruginosa strain: identification of the BpeEF-OprC chloramphenicol and trimethoprim efflux pump of Burkholderia pseudomallei 1026b. Antimicrob Agents Chemother 2006;50:3460-3
  • Robertson GT, Doyle TB, Du Q, A Novel indole compound that inhibits Pseudomonas aeruginosa growth by targeting MreB is a substrate for MexAB-OprM. J Bacteriol 2007;189(19):6870-81
  • Chuanchuen R, Karkhoff-Schweizer RR, Schweizer HP. High-level triclosan resistance in Pseudomonas aeruginosa is solely due to efflux. Am J Infect Control 2003;31(2):124-7
  • Schweizer HP. When it comes to drug discovery not all Gram-negative bacterial biodefense pathogens are created equal: Burkholderia pseudomallei is different. Microb Biotechnol 2012; [Epub ahead of print]

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.