Journal of Microbiology and Biotechnology
The Korean Society for Microbiology and Biotechnology publishes the Journal of Microbiology and Biotechnology.

2019 ; Vol.29-1: 1~10

AuthorUmji Choi, Chang-Ro Lee
TitleAntimicrobial Agents That Inhibit the Outer Membrane Assembly Machines of Gram-Negative Bacteria
PublicationInfo J. Microbiol. Biotechnol.2019 ; Vol.29-1
AbstractGram-negative pathogens, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, pose a serious threat to public health worldwide, due to high rates of antibiotic resistance and the lack of development of novel antimicrobial agents targeting Gram-negative bacteria. The outer membrane (OM) of Gram-negative bacteria is a unique architecture that acts as a potent permeability barrier against toxic molecules, such as antibiotics. The OM is composed of phospholipids, lipopolysaccharide (LPS), outer membrane β-barrel proteins (OMP), and lipoproteins. These components are synthesized in the cytoplasm or in the inner membrane, and are then selectively transported to the OM by the specific transport machines, including the Lol, BAM, and Lpt pathways. In this review, we summarize recent studies on the assembly systems of OM components and analyze studies for the development of inhibitors that target these systems. These analyses show that OM assembly machines have the potential to be a novel attractive drug target of Gram-negative bacteria.
Full-Text
Key_wordAntimicrobial agents, outer membrane assembly machine, lipoprotein, LPS, OMP, phospholipid
References
  1. Patel DS, Qi Y, Im W. 2017. Modeling and simulation of bacterial outer membranes and interactions with membrane proteins. Curr. Opin. Struct. Biol. 43: 131-140.
    Pubmed CrossRef
  2. May KL, Silhavy TJ. 2017. Making a membrane on the other side of the wall. Biochim. Biophys. Acta 1862: 1386-1393.
    Pubmed CrossRef Pubmed Central
  3. Grabowicz M. 2018. Lipoprotein transport: greasing the machines of outer membrane biogenesis: re-examining lipoprotein transport mechanisms among diverse Gramnegative bacteria while exploring new discoveries and questions. Bioessays 40: e1700187
    Pubmed CrossRef
  4. Typas A, Banzhaf M, van den Berg van Saparoea B, Verheul J, Biboy J, Nichols RJ, et al. 2010. Regulation of peptidoglycan synthesis by outer-membrane proteins. Cell 143: 1097-1109.
    Pubmed CrossRef Pubmed Central
  5. Paradis-Bleau C, Markovski M, Uehara T, Lupoli TJ, Walker S, Kahne DE, et al. 2010. Lipoprotein cofactors located in the outer membrane activate bacterial cell wall polymerases. Cell 143: 1110-1120.
    Pubmed CrossRef Pubmed Central
  6. Liu R, Ochman H. 2007. Stepwise formation of the bacterial flagellar system. Proc. Natl. Acad. Sci. USA 104: 7116-7121.
    Pubmed CrossRef Pubmed Central
  7. Hospenthal MK, Costa TRD, Waksman G. 2017. A comprehensive guide to pilus biogenesis in Gram-negative bacteria. Nat. Rev. Microbiol. 15: 365-379.
    Pubmed CrossRef
  8. Durand E, Nguyen VS, Zoued A, Logger L, Pehau-Arnaudet G, Aschtgen MS, et al. 2015. Biogenesis and structure of a type VI secretion membrane core complex. Nature 523: 555-560.
    Pubmed CrossRef
  9. Dong C, Beis K, Nesper J, Brunkan-Lamontagne AL, Clarke BR, Whitfield C, et al. 2 006. Wza t he t r anslocon f or E. coli capsular polysaccharides defines a new class of membrane protein. Nature 444: 226-229.
    Pubmed CrossRef Pubmed Central
  10. Zeth K, Thein M. 2010. Porins in prokaryotes and eukaryotes:common themes and variations. Biochem. J. 431: 13-22.
    Pubmed CrossRef
  11. Lee CR, Lee JH, Park M, Park KS, Bae IK, Kim YB et al. 2017. Biology of Acinetobacter baumannii: pathogenesis, antibiotic resistance mechanisms, and prospective treatment options. Front. Cell. Infect. Microbiol. 7: 55.
    Pubmed CrossRef Pubmed Central
  12. O'Shea R, Moser HE. 2008. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51: 2871-2878.
    Pubmed CrossRef
  13. Lee CR, Cho IH, Jeong BC, Lee SH. 2013. Strategies to minimize antibiotic resistance. Int. J. Environ. Res. Public Health 10: 4274-4305.
    Pubmed CrossRef Pubmed Central
  14. Lee CR, Lee JH, Park KS, Jeon JH, Kim YB, Cha CJ, et al. 2017. Antimicrobial resistance of hypervirulent Klebsiella pneumoniae: epidemiology, hypervirulence-associated determinants, and resistance mechanisms. Front. Cell. Infect. Microbiol. 7: 483.
    CrossRef
  15. Konovalova A, Silhavy TJ. 2015. Outer membrane lipoprotein biogenesis: Lol is not the end. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 370: 20150030.
    Pubmed CrossRef Pubmed Central
  16. Narita SI, Tokuda H. 2017. Bacterial lipoproteins; biogenesis, sorting and quality control. Biochim. Biophys. Acta 1862:1414-1423.
    Pubmed CrossRef
  17. Yamaguchi K, Yu F, Inouye M. 1988. A single amino acid determinant of the membrane localization of lipoproteins in E. coli. Cell 53: 423-432.
    CrossRef
  18. Yakushi T, Masuda K, Narita S, Matsuyama S, Tokuda H. 2000. A n ew ABC t r ansporter mediating the d etachment of lipid-modified proteins from membranes. Nat. Cell. Biol. 2:212-218.
    Pubmed CrossRef
  19. Yakushi T, Yokota N, Matsuyama S, Tokuda H. 1998. LolAdependent release of a lipid-modified protein from the inner membrane of Escherichia coli requires nucleoside triphosphate. J. Biol. Chem. 273: 32576-32581.
    Pubmed CrossRef
  20. Mizutani M, Mukaiyama K, Xiao J, Mori M, Satou R, Narita S, et al. 2013. Functional differentiation of structurally similar membrane subunits of the ABC transporter LolCDE complex. FEBS Lett. 587: 23-29.
    Pubmed CrossRef
  21. Okuda S, Tokuda H. 2009. Model of mouth-to-mouth transfer of bacterial lipoproteins through inner membrane LolC, periplasmic LolA, and outer membrane LolB. Proc. Natl. Acad. Sci. USA 106: 5877-5882.
    Pubmed CrossRef Pubmed Central
  22. Takeda K, Miyatake H, Yokota N, Matsuyama S, Tokuda H, Miki K. 2003. Crystal structures of bacterial lipoprotein localization factors, LolA and LolB. EMBO J. 22: 3199-3209.
    Pubmed CrossRef Pubmed Central
  23. Hayashi Y, Tsurumizu R, Tsukahara J, Takeda K, Narita S, Mori M, et al. 2014. Roles of the protruding loop of factor B essential for the localization of lipoproteins (LolB) in the anchoring of bacterial triacylated proteins to the outer membrane. J. Biol. Chem. 289: 10530-10539.
    Pubmed CrossRef Pubmed Central
  24. Walther DM, Rapaport D, Tommassen J. 2009. Biogenesis of β-barrel membrane proteins in bacteria and eukaryotes:evolutionary conservation and divergence. Cell. Mol. Life Sci. 66: 2789-2804.
    Pubmed CrossRef Pubmed Central
  25. Noinaj N, Rollauer SE, Buchanan SK. 2015. The β-barrel membrane protein insertase machinery from Gram-negative bacteria. Curr. Opin. Struct. Biol. 31: 35-42.
    Pubmed CrossRef Pubmed Central
  26. Voulhoux R, Bos MP, Geurtsen J, Mols M, Tommassen J. 2003. Role of a highly conserved bacterial protein in outer membrane protein assembly. Science 299: 262-265.
    Pubmed CrossRef
  27. Kim S , Malinver ni J C, S liz P, S ilhavy T J, H ar rison S C, Kahne D. 2007. Structure and function of an essential component of the outer membrane protein assembly machine. Science 317: 961-964.
    Pubmed CrossRef
  28. Misra R, Stikeleather R, Gabriele R. 2015. In vivo roles of BamA, BamB and BamD in the biogenesis of BamA, a core protein of the β-barrel assembly machine of Escherichia coli. J. Mol. Biol. 427: 1061-1074.
    Pubmed CrossRef Pubmed Central
  29. Hagan CL, Westwood DB, Kahne D. 2013. Bam lipoproteins assemble BamA in vitro. Biochemistry 52: 6108-6113.
    Pubmed CrossRef Pubmed Central
  30. Sperandeo P, Martorana AM, Polissi A. 2017. The lipopolysaccharide transport (Lpt) machinery: a nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria. J. Biol. Chem. 292:17981-17990.
    Pubmed CrossRef Pubmed Central
  31. Suits MD, Sperandeo P, Deho G, Polissi A, Jia Z. 2008. Novel structure of the conserved gram-negative lipopolysaccharide transport protein A and mutagenesis analysis. J. Mol. Biol. 380: 476-488.
    Pubmed CrossRef
  32. Merten JA, Schultz KM, Klug CS. 2012. Concentrationdependent oligomerization and oligomeric arrangement of LptA. Protein Sci. 21: 211-218.
    Pubmed CrossRef Pubmed Central
  33. Freinkman E, Okuda S, Ruiz N, Kahne D. 2012. Regulated assembly of the transenvelope protein complex required for lipopolysaccharide export. Biochemistry 51: 4800-4806.
    Pubmed CrossRef Pubmed Central
  34. Okuda S, Freinkman E, Kahne D. 2012. Cytoplasmic ATP hydrolysis powers transport of lipopolysaccharide across the periplasm in E. coli. Science 338: 1214-1217.
    Pubmed CrossRef Pubmed Central
  35. Tran AX, Dong C, Whitfield C. 2010. Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli. J. Biol. Chem. 285: 33529-33539.
    Pubmed CrossRef Pubmed Central
  36. Laguri C, Sperandeo P, Pounot K, Ayala I, Silipo A, Bougault CM, et al. 2017. Interaction of lipopolysaccharides at i nter molecular sites o f the periplasmic L pt t r ansport assembly. Sci. Rep. 7: 9715.
    Pubmed CrossRef Pubmed Central
  37. Schultz KM, Lundquist TJ, Klug CS. 2017. Lipopolysaccharide binding to the periplasmic protein LptA. Protein Sci. 26:1517-1523.
    Pubmed CrossRef Pubmed Central
  38. Freinkman E, Chng SS, Kahne D. 2011. The complex that inserts lipopolysaccharide into the bacterial outer membrane forms a two-protein plug-and-barrel. Proc. Natl. Acad. Sci. USA 108: 2486-2491.
    Pubmed CrossRef Pubmed Central
  39. Gu Y, Stansfeld PJ, Zeng Y, Dong H, Wang W, Dong C. 2015. Lipopolysaccharide is inserted into the outer membrane through an intramembrane hole, a lumen gate, and the lateral opening of LptD. Structure 23: 496-504.
    Pubmed CrossRef Pubmed Central
  40. Li X, Gu Y, Dong H, Wang W, Dong C. 2015. Trapped lipopolysaccharide and LptD intermediates reveal lipopolysaccharide translocation steps across the Escherichia coli outer membrane. Sci. Rep. 5: 11883.
    Pubmed CrossRef Pubmed Central
  41. Sperandeo P, Martorana AM, Polissi A. 2017. Lipopolysaccharide biogenesis and transport at the outer membrane of Gram-negative bacteria. Biochim. Biophys. Acta 1862: 14511460.
  42. Chng SS, Xue M, Garner RA, Kadokura H, Boyd D, Beckwith J, et al. 2012. Disulfide rearrangement triggered by translocon assembly controls lipopolysaccharide export. Science 337: 1665-1668.
    Pubmed CrossRef Pubmed Central
  43. Chng SS, Ruiz N, Chimalakonda G, Silhavy TJ, Kahne D. 2010. Characterization of the two-protein complex in Escherichia coli responsible for lipopolysaccharide assembly at the outer membrane. Proc. Natl. Acad. Sci. USA 107: 53635368.
    Pubmed CrossRef Pubmed Central
  44. Chimalakonda G, Ruiz N, Chng SS, Garner RA, Kahne D, Silhavy TJ. 2011. Lipoprotein LptE is required for the assembly of LptD by the beta-barrel assembly machine in the outer membrane of Escherichia coli. Proc. Natl. Acad. Sci. USA 108: 2492-2497.
    Pubmed CrossRef Pubmed Central
  45. Malojcic G, Andres D, Grabowicz M, George AH, Ruiz N, Silhavy TJ, et al. 2014. LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface. Proc. Natl. Acad. Sci. USA 111: 9467-9472.
    Pubmed CrossRef Pubmed Central
  46. Malinverni JC, Silhavy TJ. 2009. An ABC transport system that m aintains lipid a symmetr y in t he g r am-negative o uter membrane. Proc. Natl. Acad. Sci. USA 106: 8009-8014.
    Pubmed CrossRef Pubmed Central
  47. Ekiert DC, Bhabha G, Isom GL, Greenan G, Ovchinnikov S, Henderson IR, et al. 2017. Architectures of lipid transport systems for the bacterial outer membrane. Cell 169: 273-285 e217.
  48. Ruiz N, Wu T, Kahne D, Silhavy TJ. 2006. Probing the barrier function of the outer membrane with chemical conditionality. ACS Chem. Biol. 1: 385-395.
    Pubmed CrossRef
  49. Dekker N. 2000. Outer-membrane phospholipase A: known structure, unknown biological function. Mol. Microbiol. 35:711-717.
    Pubmed CrossRef
  50. Bishop RE, Gibbons HS, Guina T, Trent MS, Miller SI, Raetz CR. 2000. Transfer of palmitate from phospholipids to lipid A in outer membranes of gram-negative bacteria. EMBO J. 19: 5071-5080.
    Pubmed CrossRef Pubmed Central
  51. Chong ZS, Woo WF, Chng SS. 2015. Osmoporin OmpC forms a complex with MlaA to maintain outer membrane lipid asymmetry in Escherichia coli. Mol. Microbiol. 98: 11331146.
    Pubmed CrossRef
  52. Dalebroux ZD, Edrozo MB, Pfuetzner RA, Ressl S, Kulasekara BR, Blanc MP et al. 2015. Delivery of cardiolipins to the Salmonella outer membrane is necessary for survival within host tissues and virulence. Cell. Host Microbe 17: 441-451.
    Pubmed CrossRef Pubmed Central
  53. Ito H, Ura A, Oyamada Y, Yoshida H, Yamagishi J, Narita S et al. 2007. A new screening method to identify inhibitors of the Lol (localization of lipoproteins) system, a novel antibacterial target. Microbiol. Immunol. 51: 263-270.
    Pubmed CrossRef
  54. Pathania R, Zlitni S, Barker C, Das R, Gerritsma DA, Lebert J, et al. 2009. Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting. Nat. Chem. Biol. 5: 849-856.
    Pubmed CrossRef
  55. Barker CA, Allison SE, Zlitni S, Nguyen ND, Das R, Melacini G, et al. 2013. Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA. Bioorg. Med. Chem. Lett. 23: 2426-2431.
    Pubmed CrossRef
  56. Iwai N, Nagai K, Wachi M. 2002. Novel S-benzylisothiourea compound that induces spherical cells in Escherichia coli probably by acting on a rod-shape-determining protein(s) other than penicillin-binding protein 2. Biosci. Biotechnol. Biochem. 66: 2658-2662.
    Pubmed CrossRef
  57. McLeod SM, Fleming PR, MacCormack K, McLaughlin RE, Whiteaker JD, Narita S, et al. 2015. Small-molecule inhibitors of gram-negative lipoprotein trafficking discovered by phenotypic screening. J. Bacteriol. 197: 1075-1082.
    Pubmed CrossRef Pubmed Central
  58. Nayar AS, Dougherty TJ, Ferguson KE, Granger BA, McWilliams L, Stacey C, et al. 2015. Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. J. Bacteriol. 197: 1726-1734.
    Pubmed CrossRef Pubmed Central
  59. Nickerson NN, Jao CC, Xu Y, Quinn J, Skippington E, Alexander MK, et al. 2018. A novel inhibitor of the LolCDE ABC transporter essential for lipoprotein trafficking in Gram-negative bacteria. Antimicrob. Agents Chemother. 62:e02151-17.
    Pubmed CrossRef Pubmed Central
  60. Sun D, Cohen S, Mani N, Murphy C, Rothstein DM. 2002. A pathway-specific cell based screening system to detect bacterial cell wall inhibitors. J. Antibiot. (Tokyo) 55: 279-287.
    CrossRef
  61. Tam C, Missiakas D. 2005. Changes in lipopolysaccharide structure induce the σE-dependent response of Escherichia coli. Mol. Microbiol. 55: 1403-1412.
    Pubmed CrossRef
  62. Lima S, Guo MS, Chaba R, Gross CA, Sauer RT. 2013. Dual molecular signals mediate the bacterial response to outermembrane stress. Science 340: 837-841.
    Pubmed CrossRef Pubmed Central
  63. Gronenberg LS, Kahne D. 2010. Development of an activity assay for discovery of inhibitors of lipopolysaccharide transport. J. Am. Chem. Soc. 132: 2518-2519.
    Pubmed CrossRef Pubmed Central
  64. Sherman DJ, Okuda S, Denny WA, Kahne D. 2013. Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli. Bioorg. Med. Chem. 21: 4846-4851.
    Pubmed CrossRef Pubmed Central
  65. Parker LL, Piwnica-Worms H. 1992. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257: 1955-1957.
    Pubmed CrossRef
  66. Kokryakov VN, Harwig SS, Panyutich EA, Shevchenko AA, Aleshina GM, Shamova OV, et al. 1993. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett. 327: 231-236.
    CrossRef
  67. Steinberg DA, Hurst MA, Fujii CA, Kung AH, Ho JF, Cheng FC, et al. 1997. Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity. Antimicrob. Agents Chemother. 41: 1738-1742.
    Pubmed CrossRef Pubmed Central
  68. Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, et al. 2010. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327: 1010-1013.
    Pubmed CrossRef
  69. Andolina G, Bencze LC, Zerbe K, Muller M, Steinmann J, Kocherla H, et al. 2018. A peptidomimetic antibiotic interacts with the periplasmic domain of LptD from Pseudomonas aeruginosa. ACS Chem. Biol. 13: 666-675.
    Pubmed CrossRef
  70. Schmidt J, Patora-Komisarska K, Moehle K, Obrecht D, Robinson JA. 2013. Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp. Bioorg. Med. Chem. 21: 5806-5810.
    Pubmed CrossRef
  71. Vetterli SU, Moehle K, Robinson JA. 2016. Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic β-hairpin peptidomimetic antibiotics containing N-methylated amino acids. Bioorg. Med. Chem. 24: 6332-6339.
    Pubmed CrossRef
  72. Zerbe K, Moehle K, Robinson JA. 2017. Protein epitope mimetics: from new antibiotics to supramolecular synthetic vaccines. Acc. Chem. Res. 50: 1323-1331.
    Pubmed CrossRef
  73. Urfer M, Bogdanovic J, Lo Monte F, Moehle K, Zerbe K, Omasits U, et al. 2016. A peptidomimetic antibiotic targets outer membrane proteins and disrupts selectively the outer membrane in Escherichia coli. J. Biol. Chem. 291: 1921-1932.
    Pubmed CrossRef Pubmed Central



Copyright © 2009 by the Korean Society for Microbiology and Biotechnology.
All right reserved. Mail to jmb@jmb.or.kr
Online ISSN: 1738-8872    Print ISSN: 1017-7825    Powered by INFOrang.co., Ltd