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EcoSal Plus

Domain 11: Antibiotic Mechanisms and Resistance

Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: John J. Psonis1,2, and David G. Thanassi3,4
  • Editors: Maria Sandkvist5, Eric Cascales6, Peter J. Christie7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794; 2: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794; 3: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794; 4: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794; 5: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; 6: CNRS Aix-Marseille Université, Mediterranean Institute of Microbiology, Marseille, France; 7: Department of Microbiology and Molecular Genetics, McGovern Medical School, Houston, Texas
  • Received 24 October 2018 Accepted 07 January 2019 Published 15 March 2019
  • Address correspondence to David G. Thanassi, [email protected]
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  • Abstract:

    The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.

  • Citation: Psonis J, Thanassi D. 2019. Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0033-2018

References

1. Nuccio SP, Bäumler AJ. 2007. Evolution of the chaperone/usher assembly pathway: fimbrial classification goes Greek. Microbiol Mol Biol Rev 71:551–575. http://dx.doi.org/10.1128/MMBR.00014-07. [PubMed]
2. Zav’yalov V, Zavialov A, Zav’yalova G, Korpela T. 2010. Adhesive organelles of Gram-negative pathogens assembled with the classical chaperone/usher machinery: structure and function from a clinical standpoint. FEMS Microbiol Rev 34:317–378. http://dx.doi.org/10.1111/j.1574-6976.2009.00201.x. [PubMed]
3. Thanassi DG, Bliska JB, Christie PJ. 2012. Surface organelles assembled by secretion systems of Gram-negative bacteria: diversity in structure and function. FEMS Microbiol Rev 36:1046–1082. http://dx.doi.org/10.1111/j.1574-6976.2012.00342.x. [PubMed]
4. Geibel S, Waksman G. 2014. The molecular dissection of the chaperone-usher pathway. Biochim Biophys Acta 1843:1559–1567. http://dx.doi.org/10.1016/j.bbamcr.2013.09.023. [PubMed]
5. Chahales P, Thanassi DG. 2015. Structure, function, and assembly of adhesive organelles by uropathogenic bacteria. Microbiol Spectr 3(5) :UTI-0018-2013. http://dx.doi.org/10.1128/microbiolspec.UTI-0018-2013. [PubMed]
6. Werneburg GT, Thanassi DG. 2018. Pili assembled by the chaperone/usher pathway in Escherichia coli and Salmonella. EcoSal Plus http://dx.doi.org/10.1128/ecosalplus.ESP-0007-2017. [PubMed]
7. van der Velden AW, Bäumler AJ, Tsolis RM, Heffron F. 1998. Multiple fimbrial adhesins are required for full virulence of Salmonella typhimurium in mice. Infect Immun 66:2803–2808. [PubMed]
8. Korea CG, Badouraly R, Prevost MC, Ghigo JM, Beloin C. 2010. Escherichia coli K-12 possesses multiple cryptic but functional chaperone-usher fimbriae with distinct surface specificities. Environ Microbiol 12:1957–1977. http://dx.doi.org/10.1111/j.1462-2920.2010.02202.x. [PubMed]
9. Felek S, Jeong JJ, Runco LM, Murray S, Thanassi DG, Krukonis ES. 2011. Contributions of chaperone/usher systems to cell binding, biofilm formation and Yersinia pestis virulence. Microbiology 157:805–818. http://dx.doi.org/10.1099/mic.0.044826-0. [PubMed]
10. Wurpel DJ, Beatson SA, Totsika M, Petty NK, Schembri MA. 2013. Chaperone-usher fimbriae of Escherichia coli. PLoS One 8:e52835. http://dx.doi.org/10.1371/journal.pone.0052835. [PubMed]
11. Roberts JA, Marklund BI, Ilver D, Haslam D, Kaack MB, Baskin G, Louis M, Möllby R, Winberg J, Normark S. 1994. The Gal(alpha 1-4)Gal-specific tip adhesin of Escherichia coli P-fimbriae is needed for pyelonephritis to occur in the normal urinary tract. Proc Natl Acad Sci U S A 91:11889–11893. http://dx.doi.org/10.1073/pnas.91.25.11889. [PubMed]
12. Zhou G, Mo WJ, Sebbel P, Min G, Neubert TA, Glockshuber R, Wu XR, Sun TT, Kong XP. 2001. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. J Cell Sci 114:4095–4103. [PubMed]
13. Eto DS, Jones TA, Sundsbak JL, Mulvey MA. 2007. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog 3:e100. http://dx.doi.org/10.1371/journal.ppat.0030100. [PubMed]
14. Mulvey MA, Lopez-Boado YS, Wilson CL, Roth R, Parks WC, Heuser J, Hultgren SJ. 1998. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282:1494–1497. http://dx.doi.org/10.1126/science.282.5393.1494. [PubMed]
15. Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. 2000. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J 19:2803–2812. http://dx.doi.org/10.1093/emboj/19.12.2803. [PubMed]
16. Pratt LA, Kolter R. 1998. Genetic analysis of Escherichia coli biofilm formation: roles of flagella, motility, chemotaxis and type I pili. Mol Microbiol 30:285–293. http://dx.doi.org/10.1046/j.1365-2958.1998.01061.x.
17. Wright KJ, Seed PC, Hultgren SJ. 2007. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol 9:2230–2241. http://dx.doi.org/10.1111/j.1462-5822.2007.00952.x. [PubMed]
18. Justice SS, Hung C, Theriot JA, Fletcher DA, Anderson GG, Footer MJ, Hultgren SJ. 2004. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci U S A 101:1333–1338. http://dx.doi.org/10.1073/pnas.0308125100. [PubMed]
19. Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. 2003. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301:105–107. http://dx.doi.org/10.1126/science.1084550. [PubMed]
20. Gaastra W, Svennerholm AM. 1996. Colonization factors of human enterotoxigenic Escherichia coli (ETEC). Trends Microbiol 4:444–452. http://dx.doi.org/10.1016/0966-842X(96)10068-8.
21. Labigne-Roussel A, Schmidt MA, Walz W, Falkow S. 1985. Genetic organization of the afimbrial adhesin operon and nucleotide sequence from a uropathogenic Escherichia coli gene encoding an afimbrial adhesin. J Bacteriol 162:1285–1292. [PubMed]
22. Garcia MI, Gounon P, Courcoux P, Labigne A, Le Bouguenec C. 1996. The afimbrial adhesive sheath encoded by the afa-3 gene cluster of pathogenic Escherichia coli is composed of two adhesins. Mol Microbiol 19:683–693. http://dx.doi.org/10.1046/j.1365-2958.1996.394935.x. [PubMed]
23. Anderson KL, Billington J, Pettigrew D, Cota E, Simpson P, Roversi P, Chen HA, Urvil P, du Merle L, Barlow PN, Medof ME, Smith RA, Nowicki B, Le Bouguénec C, Lea SM, Matthews S. 2004. An atomic resolution model for assembly, architecture, and function of the Dr adhesins. Mol Cell 15:647–657. http://dx.doi.org/10.1016/j.molcel.2004.08.003. [PubMed]
24. Titball RW, Howells AM, Oyston PC, Williamson ED. 1997. Expression of the Yersinia pestis capsular antigen (F1 antigen) on the surface of an aroA mutant of Salmonella typhimurium induces high levels of protection against plague. Infect Immun 65:1926–1930. [PubMed]
25. Du Y, Rosqvist R, Forsberg A. 2002. Role of fraction 1 antigen of Yersinia pestis in inhibition of phagocytosis. Infect Immun 70:1453–1460. http://dx.doi.org/10.1128/IAI.70.3.1453-1460.2002. [PubMed]
26. Liu F, Chen H, Galván EM, Lasaro MA, Schifferli DM. 2006. Effects of Psa and F1 on the adhesive and invasive interactions of Yersinia pestis with human respiratory tract epithelial cells. Infect Immun 74:5636–5644. http://dx.doi.org/10.1128/IAI.00612-06. [PubMed]
27. Thomas WE, Nilsson LM, Forero M, Sokurenko EV, Vogel V. 2004. Shear-dependent ‘stick-and-roll’ adhesion of type 1 fimbriated Escherichia coli. Mol Microbiol 53:1545–1557. http://dx.doi.org/10.1111/j.1365-2958.2004.04226.x. [PubMed]
28. Le Trong I, Aprikian P, Kidd BA, Forero-Shelton M, Tchesnokova V, Rajagopal P, Rodriguez V, Interlandi G, Klevit R, Vogel V, Stenkamp RE, Sokurenko EV, Thomas WE. 2010. Structural basis for mechanical force regulation of the adhesin FimH via finger trap-like beta sheet twisting. Cell 141:645–655. http://dx.doi.org/10.1016/j.cell.2010.03.038. [PubMed]
29. Sauer MM, Jakob RP, Eras J, Baday S, Eriş D, Navarra G, Bernèche S, Ernst B, Maier T, Glockshuber R. 2016. Catch-bond mechanism of the bacterial adhesin FimH. Nat Commun 7:10738. http://dx.doi.org/10.1038/ncomms10738. [PubMed]
30. Jass J, Schedin S, Fällman E, Ohlsson J, Nilsson UJ, Uhlin BE, Axner O. 2004. Physical properties of Escherichia coli P pili measured by optical tweezers. Biophys J 87:4271–4283. http://dx.doi.org/10.1529/biophysj.104.044867. [PubMed]
31. Fällman E, Schedin S, Jass J, Uhlin BE, Axner O. 2005. The unfolding of the P pili quaternary structure by stretching is reversible,not plastic. EMBO Rep 6:52–56. http://dx.doi.org/10.1038/sj.embor.7400310. [PubMed]
32. Andersson M, Axner O, Almqvist F, Uhlin BE, Fällman E. 2008. Physical properties of biopolymers assessed by optical tweezers: analysis of folding and refolding of bacterial pili. Chemphyschem 9:221–235. http://dx.doi.org/10.1002/cphc.200700389. [PubMed]
33. Jacob-Dubuisson F, Striker R, Hultgren SJ. 1994. Chaperone-assisted self-assembly of pili independent of cellular energy. J Biol Chem 269:12447–12455. [PubMed]
34. Thanassi DG, Stathopoulos C, Karkal A, Li H. 2005. Protein secretion in the absence of ATP: the autotransporter, two-partner secretion and chaperone/usher pathways of gram-negative bacteria. Mol Membr Biol 22:63–72. http://dx.doi.org/10.1080/09687860500063290.
35. Totsika M, Heras B, Wurpel DJ, Schembri MA. 2009. Characterization of two homologous disulfide bond systems involved in virulence factor biogenesis in uropathogenic Escherichia coli CFT073. J Bacteriol 191:3901–3908. http://dx.doi.org/10.1128/JB.00143-09.
36. Crespo MD, Puorger C, Schärer MA, Eidam O, Grütter MG, Capitani G, Glockshuber R. 2012. Quality control of disulfide bond formation in pilus subunits by the chaperone FimC. Nat Chem Biol 8:707–713. http://dx.doi.org/10.1038/nchembio.1019.
37. Pilipczuk J, Zalewska-Piątek B, Bruździak P, Czub J, Wieczór M, Olszewski M, Wanarska M, Nowicki B, Augustin-Nowacka D, Piątek R. 2017. Role of the disulfide bond in stabilizing and folding of the fimbrial protein DraE from uropathogenic Escherichia coli. J Biol Chem 292:16136–16149. http://dx.doi.org/10.1074/jbc.M117.785477.
38. Alonso-Caballero A, Schönfelder J, Poly S, Corsetti F, De Sancho D, Artacho E, Perez-Jimenez R. 2018. Mechanical architecture and folding of E. coli type 1 pilus domains. Nat Commun 9:2758. http://dx.doi.org/10.1038/s41467-018-05107-6.
39. Sauer FG, Fütterer K, Pinkner JS, Dodson KW, Hultgren SJ, Waksman G. 1999. Structural basis of chaperone function and pilus biogenesis. Science 285:1058–1061. http://dx.doi.org/10.1126/science.285.5430.1058.
40. Choudhury D, Thompson A, Stojanoff V, Langermann S, Pinkner J, Hultgren SJ, Knight SD. 1999. X-ray structure of the FimC-FimH chaperone-adhesin complex from uropathogenic Escherichia coli. Science 285:1061–1066. http://dx.doi.org/10.1126/science.285.5430.1061.
41. Jones CH, Danese PN, Pinkner JS, Silhavy TJ, Hultgren SJ. 1997. The chaperone-assisted membrane release and folding pathway is sensed by two signal transduction systems. EMBO J 16:6394–6406. http://dx.doi.org/10.1093/emboj/16.21.6394.
42. Bann JG, Pinkner JS, Frieden C, Hultgren SJ. 2004. Catalysis of protein folding by chaperones in pathogenic bacteria. Proc Natl Acad Sci U S A 101:17389–17393. http://dx.doi.org/10.1073/pnas.0408072101.
43. Sauer FG, Pinkner JS, Waksman G, Hultgren SJ. 2002. Chaperone priming of pilus subunits facilitates a topological transition that drives fiber formation. Cell 111:543–551. http://dx.doi.org/10.1016/S0092-8674(02)01050-4.
44. Zavialov AV, Berglund J, Pudney AF, Fooks LJ, Ibrahim TM, MacIntyre S, Knight SD. 2003. Structure and biogenesis of the capsular F1 antigen from Yersinia pestis: preserved folding energy drives fiber formation. Cell 113:587–596. http://dx.doi.org/10.1016/S0092-8674(03)00351-9.
45. Zavialov AV, Tischenko VM, Fooks LJ, Brandsdal BO, Aqvist J, Zav’yalov VP, Macintyre S, Knight SD. 2005. Resolving the energy paradox of chaperone/usher-mediated fibre assembly. Biochem J 389:685–694. http://dx.doi.org/10.1042/BJ20050426.
46. Remaut H, Rose RJ, Hannan TJ, Hultgren SJ, Radford SE, Ashcroft AE, Waksman G. 2006. Donor-strand exchange in chaperone-assisted pilus assembly proceeds through a concerted beta strand displacement mechanism. Mol Cell 22:831–842. http://dx.doi.org/10.1016/j.molcel.2006.05.033.
47. Nishiyama M, Ishikawa T, Rechsteiner H, Glockshuber R. 2008. Reconstitution of pilus assembly reveals a bacterial outer membrane catalyst. Science 320:376–379. http://dx.doi.org/10.1126/science.1154994.
48. Saulino ET, Thanassi DG, Pinkner JS, Hultgren SJ. 1998. Ramifications of kinetic partitioning on usher-mediated pilus biogenesis. EMBO J 17:2177–2185. http://dx.doi.org/10.1093/emboj/17.8.2177.
49. Nishiyama M, Glockshuber R. 2010. The outer membrane usher guarantees the formation of functional pili by selectively catalyzing donor-strand exchange between subunits that are adjacent in the mature pilus. J Mol Biol 396:1–8. http://dx.doi.org/10.1016/j.jmb.2009.12.005.
50. Li Q, Ng TW, Dodson KW, So SS, Bayle KM, Pinkner JS, Scarlata S, Hultgren SJ, Thanassi DG. 2010. The differential affinity of the usher for chaperone-subunit complexes is required for assembly of complete pili. Mol Microbiol 76:159–172. http://dx.doi.org/10.1111/j.1365-2958.2010.07089.x.
51. Allen WJ, Phan G, Hultgren SJ, Waksman G. 2013. Dissection of pilus tip assembly by the FimD usher monomer. J Mol Biol 425:958–967. http://dx.doi.org/10.1016/j.jmb.2012.12.024. [PubMed]
52. Nishiyama M, Horst R, Eidam O, Herrmann T, Ignatov O, Vetsch M, Bettendorff P, Jelesarov I, Grütter MG, Wüthrich K, Glockshuber R, Capitani G. 2005. Structural basis of chaperone-subunit complex recognition by the type 1 pilus assembly platform FimD. EMBO J 24:2075–2086. http://dx.doi.org/10.1038/sj.emboj.7600693. [PubMed]
53. Remaut H, Tang C, Henderson NS, Pinkner JS, Wang T, Hultgren SJ, Thanassi DG, Waksman G, Li H. 2008. Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. Cell 133:640–652. http://dx.doi.org/10.1016/j.cell.2008.03.033. [PubMed]
54. Huang Y, Smith BS, Chen LX, Baxter RH, Deisenhofer J. 2009. Insights into pilus assembly and secretion from the structure and functional characterization of usher PapC. Proc Natl Acad Sci U S A 106:7403–7407. http://dx.doi.org/10.1073/pnas.0902789106. [PubMed]
55. Phan G, Remaut H, Wang T, Allen WJ, Pirker KF, Lebedev A, Henderson NS, Geibel S, Volkan E, Yan J, Kunze MB, Pinkner JS, Ford B, Kay CW, Li H, Hultgren SJ, Thanassi DG, Waksman G. 2011. Crystal structure of the FimD usher bound to its cognate FimC-FimH substrate. Nature 474:49–53. http://dx.doi.org/10.1038/nature10109. [PubMed]
56. Mapingire OS, Henderson NS, Duret G, Thanassi DG, Delcour AH. 2009. Modulating effects of the plug, helix, and N- and C-terminal domains on channel properties of the PapC usher. J Biol Chem 284:36324–36333. http://dx.doi.org/10.1074/jbc.M109.055798. [PubMed]
57. Werneburg GT, Henderson NS, Portnoy EB, Sarowar S, Hultgren SJ, Li H, Thanassi DG. 2015. The pilus usher controls protein interactions via domain masking and is functional as an oligomer. Nat Struct Mol Biol 22:540–546. http://dx.doi.org/10.1038/nsmb.3044. [PubMed]
58. Volkan E, Ford BA, Pinkner JS, Dodson KW, Henderson NS, Thanassi DG, Waksman G, Hultgren SJ. 2012. Domain activities of PapC usher reveal the mechanism of action of an Escherichia coli molecular machine. Proc Natl Acad Sci U S A 109:9563–9568. http://dx.doi.org/10.1073/pnas.1207085109. [PubMed]
59. Omattage NS, Deng Z, Pinkner JS, Dodson KW, Almqvist F, Yuan P, Hultgren SJ. 2018. Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli. Nat Microbiol 3:1362–1368. http://dx.doi.org/10.1038/s41564-018-0255-y. [PubMed]
60. Du M, Yuan Z, Yu H, Henderson N, Sarowar S, Zhao G, Werneburg GT, Thanassi DG, Li H. 2018. Handover mechanism of the growing pilus by the bacterial outer-membrane usher FimD. Nature 562:444–447. http://dx.doi.org/10.1038/s41586-018-0587-z. [PubMed]
61. Hospenthal MK, Zyla D, Costa TRD, Redzej A, Giese C, Lillington J, Glockshuber R, Waksman G. 2017. The cryoelectron microscopy structure of the type 1 chaperone-usher pilus rod. Structure 25:1829–1838.e4. http://dx.doi.org/10.1016/j.str.2017.10.004. [PubMed]
62. Hospenthal MK, Redzej A, Dodson K, Ukleja M, Frenz B, Rodrigues C, Hultgren SJ, DiMaio F, Egelman EH, Waksman G. 2016. Structure of a chaperone-usher pilus reveals the molecular basis of rod uncoiling. Cell 164:269–278. http://dx.doi.org/10.1016/j.cell.2015.11.049. [PubMed]
63. Spaulding CN, Schreiber HL IV, Zheng W, Dodson KW, Hazen JE, Conover MS, Wang F, Svenmarker P, Luna-Rico A, Francetic O, Andersson M, Hultgren S, Egelman EH. 2018. Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions. eLife 7:e31662. http://dx.doi.org/10.7554/eLife.31662. [PubMed]
64. Fauci AS, Morens DM. 2012. The perpetual challenge of infectious diseases. N Engl J Med 366:454–461. http://dx.doi.org/10.1056/NEJMra1108296. [PubMed]
65. World Health Organization. 2014. Antimicrobial Resistance: Global Report on Surveillance. WHO, Geneva, Switzerland. https://www.who.int/drugresistance/documents/surveillancereport/en/
66. Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ. 2008. The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6:17–27. http://dx.doi.org/10.1038/nrmicro1818. [PubMed]
67. Allen RC, Popat R, Diggle SP, Brown SP. 2014. Targeting virulence: can we make evolution-proof drugs? Nat Rev Microbiol 12:300–308. http://dx.doi.org/10.1038/nrmicro3232. [PubMed]
68. Zambelloni R, Marquez R, Roe AJ. 2015. Development of antivirulence compounds: a biochemical review. Chem Biol Drug Des 85:43–55. http://dx.doi.org/10.1111/cbdd.12430. [PubMed]
69. Paharik AE, Schreiber HL IV, Spaulding CN, Dodson KW, Hultgren SJ. 2017. Narrowing the spectrum: the new frontier of precision antimicrobials. Genome Med 9:110. http://dx.doi.org/10.1186/s13073-017-0504-3. [PubMed]
70. Svennerholm AM, Tobias J. 2008. Vaccines against enterotoxigenic Escherichia coli. Expert Rev Vaccines 7:795–804. http://dx.doi.org/10.1586/14760584.7.6.795. [PubMed]
71. van der Woude MW, Bäumler AJ. 2004. Phase and antigenic variation in bacteria. Clin Microbiol Rev 17:581–611. http://dx.doi.org/10.1128/CMR.17.3.581-611.2004. [PubMed]
72. Langermann S, Palaszynski S, Barnhart M, Auguste G, Pinkner JS, Burlein J, Barren P, Koenig S, Leath S, Jones CH, Hultgren SJ. 1997. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276:607–611. http://dx.doi.org/10.1126/science.276.5312.607. [PubMed]
73. Thankavel K, Madison B, Ikeda T, Malaviya R, Shah AH, Arumugam PM, Abraham SN. 1997. Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection. J Clin Invest 100:1123–1136. http://dx.doi.org/10.1172/JCI119623. [PubMed]
74. Langermann S, Möllby R, Burlein JE, Palaszynski SR, Auguste CG, DeFusco A, Strouse R, Schenerman MA, Hultgren SJ, Pinkner JS, Winberg J, Guldevall L, Söderhäll M, Ishikawa K, Normark S, Koenig S. 2000. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J Infect Dis 181:774–778. http://dx.doi.org/10.1086/315258. [PubMed]
75. Roberts JA, Kaack MB, Baskin G, Chapman MR, Hunstad DA, Pinkner JS, Hultgren SJ. 2004. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J Urol 171:1682–1685. http://dx.doi.org/10.1097/01.ju.0000116123.05160.43. [PubMed]
76. Poggio TV, La Torre JL, Scodeller EA. 2006. Intranasal immunization with a recombinant truncated FimH adhesin adjuvanted with CpG oligodeoxynucleotides protects mice against uropathogenic Escherichia coli challenge. Can J Microbiol 52:1093–1102. http://dx.doi.org/10.1139/w06-065. [PubMed]
77. Bameri Z, Asadi Karam MR, Habibi M, Ehsani P, Bouzari S. 2018. Determination immunogenic property of truncated MrpH.FliC as a vaccine candidate against urinary tract infections caused by Proteus mirabilis. Microb Pathog 114:99–106. http://dx.doi.org/10.1016/j.micpath.2017.11.015. [PubMed]
78. Savarino SJ, McKenzie R, Tribble DR, Porter CK, O’Dowd A, Cantrell JA, Sincock SA, Poole ST, DeNearing B, Woods CM, Kim H, Grahek SL, Brinkley C, Crabb JH, Bourgeois AL. 2017. Prophylactic efficacy of hyperimmune bovine colostral antiadhesin antibodies against enterotoxigenic Escherichia coli diarrhea: a randomized, double-blind, placebo-controlled, phase 1 trial. J Infect Dis 216:7–13. http://dx.doi.org/10.1093/infdis/jix144. [PubMed]
79. Tchesnokova V, Aprikian P, Kisiela D, Gowey S, Korotkova N, Thomas W, Sokurenko E. 2011. Type 1 fimbrial adhesin FimH elicits an immune response that enhances cell adhesion of Escherichia coli. Infect Immun 79:3895–3904. http://dx.doi.org/10.1128/IAI.05169-11. [PubMed]
80. Kisiela DI, Avagyan H, Friend D, Jalan A, Gupta S, Interlandi G, Liu Y, Tchesnokova V, Rodriguez VB, Sumida JP, Strong RK, Wu XR, Thomas WE, Sokurenko EV. 2015. Inhibition and reversal of microbial attachment by an antibody with parasteric activity against the FimH adhesin of uropathogenic E. coli. PLoS Pathog 11:e1004857. http://dx.doi.org/10.1371/journal.ppat.1004857. [PubMed]
81. Klein T, Abgottspon D, Wittwer M, Rabbani S, Herold J, Jiang X, Kleeb S, Lüthi C, Scharenberg M, Bezençon J, Gubler E, Pang L, Smiesko M, Cutting B, Schwardt O, Ernst B. 2010. FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. J Med Chem 53:8627–8641. http://dx.doi.org/10.1021/jm101011y. [PubMed]
82. Cusumano CK, Pinkner JS, Han Z, Greene SE, Ford BA, Crowley JR, Henderson JP, Janetka JW, Hultgren SJ. 2011. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med 3:109ra115. http://dx.doi.org/10.1126/scitranslmed.3003021. [PubMed]
83. Jiang X, Abgottspon D, Kleeb S, Rabbani S, Scharenberg M, Wittwer M, Haug M, Schwardt O, Ernst B. 2012. Antiadhesion therapy for urinary tract infections—a balanced PK/PD profile proved to be key for success. J Med Chem 55:4700–4713. http://dx.doi.org/10.1021/jm300192x. [PubMed]
84. Totsika M, Kostakioti M, Hannan TJ, Upton M, Beatson SA, Janetka JW, Hultgren SJ, Schembri MA. 2013. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J Infect Dis 208:921–928. http://dx.doi.org/10.1093/infdis/jit245. [PubMed]
85. Spaulding CN, Klein RD, Ruer S, Kau AL, Schreiber HL, Cusumano ZT, Dodson KW, Pinkner JS, Fremont DH, Janetka JW, Remaut H, Gordon JI, Hultgren SJ. 2017. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546:528–532.
86. Guiton PS, Cusumano CK, Kline KA, Dodson KW, Han Z, Janetka JW, Henderson JP, Caparon MG, Hultgren SJ. 2012. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrob Agents Chemother 56:4738–4745. http://dx.doi.org/10.1128/AAC.00447-12. [PubMed]
87. Mayer K, Eris D, Schwardt O, Sager CP, Rabbani S, Kleeb S, Ernst B. 2017. Urinary tract infection: which conformation of the bacterial lectin FimH is therapeutically relevant? J Med Chem 60:5646–5662. http://dx.doi.org/10.1021/acs.jmedchem.7b00342. [PubMed]
88. Sattigeri JA, Garg M, Bhateja P, Soni A, Rauf ARA, Gupta M, Deshmukh MS, Jain T, Alekar N, Barman TK, Jha P, Chaira T, Bambal RB, Upadhyay DJ, Nishi T. 2018. Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors. Bioorg Med Chem Lett 28:2993–2997. http://dx.doi.org/10.1016/j.bmcl.2018.06.017. [PubMed]
89. Salminen A, Loimaranta V, Joosten JA, Khan AS, Hacker J, Pieters RJ, Finne J. 2007. Inhibition of P-fimbriated Escherichia coli adhesion by multivalent galabiose derivatives studied by a live-bacteria application of surface plasmon resonance. J Antimicrob Chemother 60:495–501. http://dx.doi.org/10.1093/jac/dkm251. [PubMed]
90. Kalas V, Hibbing ME, Maddirala AR, Chugani R, Pinkner JS, Mydock-McGrane LK, Conover MS, Janetka JW, Hultgren SJ. 2018. Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection. Proc Natl Acad Sci U S A 115:E2819–E2828. http://dx.doi.org/10.1073/pnas.1720140115. [PubMed]
91. Brument S, Sivignon A, Dumych TI, Moreau N, Roos G, Guérardel Y, Chalopin T, Deniaud D, Bilyy RO, Darfeuille-Michaud A, Bouckaert J, Gouin SG. 2013. Thiazolylaminomannosides as potent antiadhesives of type 1 piliated Escherichia coli isolated from Crohn’s disease patients. J Med Chem 56:5395–5406. http://dx.doi.org/10.1021/jm400723n. [PubMed]
92. Sivignon A, Yan X, Alvarez Dorta D, Bonnet R, Bouckaert J, Fleury E, Bernard J, Gouin SG, Darfeuille-Michaud A, Barnich N. 2015. Development of heptylmannoside-based glycoconjugate antiadhesive compounds against adherent-invasive Escherichia coli bacteria associated with Crohn’s disease. mBio 6:e01298-15. http://dx.doi.org/10.1128/mBio.01298-15. [PubMed]
93. Chalopin T, Alvarez Dorta D, Sivignon A, Caudan M, Dumych TI, Bilyy RO, Deniaud D, Barnich N, Bouckaert J, Gouin SG. 2016. Second generation of thiazolylmannosides, FimH antagonists for E. coli-induced Crohn’s disease. Org Biomol Chem 14:3913–3925. http://dx.doi.org/10.1039/C6OB00424E. [PubMed]
94. Sivignon A, Bouckaert J, Bernard J, Gouin SG, Barnich N. 2017. The potential of FimH as a novel therapeutic target for the treatment of Crohn’s disease. Expert Opin Ther Targets 21:837–847. http://dx.doi.org/10.1080/14728222.2017.1363184. [PubMed]
95. Almant M, Moreau V, Kovensky J, Bouckaert J, Gouin SG. 2011. Clustering of Escherichia coli type-1 fimbrial adhesins by using multimeric heptyl α-d-mannoside probes with a carbohydrate core. Chemistry 17:10029–10038. http://dx.doi.org/10.1002/chem.201100515. [PubMed]
96. Schierholt A, Hartmann M, Lindhorst TK. 2011. Bi- and trivalent glycopeptide mannopyranosides as inhibitors of type 1 fimbriae-mediated bacterial adhesion: variation of valency, aglycon and scaffolding. Carbohydr Res 346:1519–1526. http://dx.doi.org/10.1016/j.carres.2011.04.023. [PubMed]
97. Richards SJ, Jones MW, Hunaban M, Haddleton DM, Gibson MI. 2012. Probing bacterial-toxin inhibition with synthetic glycopolymers prepared by tandem post-polymerization modification: role of linker length and carbohydrate density. Angew Chem Int Ed Engl 51:7812–7816. http://dx.doi.org/10.1002/anie.201202945. [PubMed]
98. Svensson A, Larsson A, Emtenäs H, Hedenström M, Fex T, Hultgren SJ, Pinkner JS, Almqvist F, Kihlberg J. 2001. Design and evaluation of pilicides: potential novel antibacterial agents directed against uropathogenic Escherichia coli. Chembiochem 2:915–918. http://dx.doi.org/10.1002/1439-7633(20011203)2:12<915::AID-CBIC915>3.0.CO;2-M.
99. Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V, Pemberton N, Hedenström M, Larsson A, Seed P, Waksman G, Hultgren SJ, Almqvist F. 2006. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci U S A 103:17897–17902. http://dx.doi.org/10.1073/pnas.0606795103. [PubMed]
100. Chorell E, Pinkner JS, Bengtsson C, Banchelin TS, Edvinsson S, Linusson A, Hultgren SJ, Almqvist F. 2012. Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study. Bioorg Med Chem 20:3128–3142. http://dx.doi.org/10.1016/j.bmc.2012.01.048. [PubMed]
101. Piatek R, Zalewska-Piatek B, Dzierzbicka K, Makowiec S, Pilipczuk J, Szemiako K, Cyranka-Czaja A, Wojciechowski M. 2013. Pilicides inhibit the FGL chaperone/usher assisted biogenesis of the Dr fimbrial polyadhesin from uropathogenic Escherichia coli. BMC Microbiol 13:131. http://dx.doi.org/10.1186/1471-2180-13-131.
102. Chorell E, Pinkner JS, Phan G, Edvinsson S, Buelens F, Remaut H, Waksman G, Hultgren SJ, Almqvist F. 2010. Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity. J Med Chem 53:5690–5695. http://dx.doi.org/10.1021/jm100470t.
103. Dang HT, Chorell E, Uvell H, Pinkner JS, Hultgren SJ, Almqvist F. 2014. Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives; antibacterial agents with antivirulence activity. Org Biomol Chem 12:1942–1956. http://dx.doi.org/10.1039/C3OB42478B.
104. Greene SE, Pinkner JS, Chorell E, Dodson KW, Shaffer CL, Conover MS, Livny J, Hadjifrangiskou M, Almqvist F, Hultgren SJ. 2014. Pilicide ec240 disrupts virulence circuits in uropathogenic Escherichia coli. mBio 5:e02038-14. http://dx.doi.org/10.1128/mBio.02038-14.
105. Lo AW, Van de Water K, Gane PJ, Chan AW, Steadman D, Stevens K, Selwood DL, Waksman G, Remaut H. 2014. Suppression of type 1 pilus assembly in uropathogenic Escherichia coli by chemical inhibition of subunit polymerization. J Antimicrob Chemother 69:1017–1026. http://dx.doi.org/10.1093/jac/dkt467.
106. Shamir ER, Warthan M, Brown SP, Nataro JP, Guerrant RL, Hoffman PS. 2010. Nitazoxanide inhibits biofilm production and hemagglutination by enteroaggregative Escherichia coli strains by blocking assembly of AafA fimbriae. Antimicrob Agents Chemother 54:1526–1533. http://dx.doi.org/10.1128/AAC.01279-09.
107. Chahales P, Hoffman PS, Thanassi DG. 2016. Nitazoxanide inhibits pilus biogenesis by interfering with folding of the usher protein in the outer membrane. Antimicrob Agents Chemother 60:2028–2038. http://dx.doi.org/10.1128/AAC.02221-15.
108. Klinth JE, Pinkner JS, Hultgren SJ, Almqvist F, Uhlin BE, Axner O. 2012. Impairment of the biomechanical compliance of P pili: a novel means of inhibiting uropathogenic bacterial infections? Eur Biophys J 41:285–295. http://dx.doi.org/10.1007/s00249-011-0784-2.
109. Mortezaei N, Singh B, Bullitt E, Uhlin BE, Andersson M. 2013. P-fimbriae in the presence of anti-PapA antibodies: new insight of antibodies action against pathogens. Sci Rep 3:3393. http://dx.doi.org/10.1038/srep03393.
110. Singh B, Mortezaei N, Uhlin BE, Savarino SJ, Bullitt E, Andersson M. 2015. Antibody-mediated disruption of the mechanics of CS20 fimbriae of enterotoxigenic Escherichia coli. Sci Rep 5:13678. http://dx.doi.org/10.1038/srep13678.
111. Singh B, Mortezaei N, Savarino SJ, Uhlin BE, Bullitt E, Andersson M. 2017. Antibodies damage the resilience of fimbriae, causing them to be stiff and tangled. J Bacteriol 199:e00665-16.
112. Brown JW, Badahdah A, Iticovici M, Vickers TJ, Alvarado DM, Helmerhorst EJ, Oppenheim FG, Mills JC, Ciorba MA, Fleckenstein JM, Bullitt E. 2018. A role for salivary peptides in the innate defense against enterotoxigenic Escherichia coli. J Infect Dis 217:1435–1441. http://dx.doi.org/10.1093/infdis/jiy032.
113. Paton AW, Morona R, Paton JC. 2000. A new biological agent for treatment of Shiga toxigenic Escherichia coli infections and dysentery in humans. Nat Med 6:265–270. http://dx.doi.org/10.1038/73111.
114. Watts RE, Tan CK, Ulett GC, Carey AJ, Totsika M, Idris A, Paton AW, Morona R, Paton JC, Schembri MA. 2012. Escherichia coli 83972 expressing a P fimbriae oligosaccharide receptor mimic impairs adhesion of uropathogenic E. coli. J Infect Dis 206:1242–1249. http://dx.doi.org/10.1093/infdis/jis493.
115. Trautner BW, Cevallos ME, Li H, Riosa S, Hull RA, Hull SI, Tweardy DJ, Darouiche RO. 2008. Increased expression of type-1 fimbriae by nonpathogenic Escherichia coli 83972 results in an increased capacity for catheter adherence and bacterial interference. J Infect Dis 198:899–906. http://dx.doi.org/10.1086/591093.
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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0033-2018
2019-03-15
2019-10-21

Abstract:

The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.

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Figures

Image of Figure 1
Figure 1

Electron micrographs of expressing type 1 pili and expressing F1 capsule . Scale bars = 500 nm. Cartoon for pilus-mediated bacterial interactions in the bladder. (i) Type 1-piliated UPEC binds to superficial umbrella cells that line the lumen of the bladder. (ii) Pilus-receptor interactions induce a signaling cascade that promotes internalization of adherent bacteria via a membrane zippering mechanism. (iii) Within bladder epithelial cells, UPEC are trafficked to membrane-bound, acidic compartments similar to lysosomes. (iv) In the superficial umbrella cells, UPEC break into the cytosol and rapidly multiply, forming intracellular biofilm-like communities. (v) Bladder cells containing large numbers of UPEC exfoliate, providing a mechanism for bacterial clearance by the flow of urine. (vi) This, however, leaves the underlying layers of immature bladder epithelial cells exposed. UPEC can invade these immature urothelial cells and persist in a quiescent stage in late endosome-like compartments, avoiding detection by immunosurveillance mechanisms. The F1 capsule plays an antiphagocytic role by preventing opsonizing antibodies from binding to the bacterial surface, blocking Fc receptor phagocytosis. More generally, expression of the F1 capsule can mask bacterial adhesins and other surface structures, preventing interactions that lead to internalization into host cells.

Citation: Psonis J, Thanassi D. 2019. Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0033-2018
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Image of Figure 2
Figure 2

The gene cluster coding for type 1 pili, along with names and functions of encoded proteins, is shown at the bottom. Upon entering the periplasm via the SecYEG general secretory machinery, nascent pilus subunits form binary complexes with the pilus chaperone (FimC), which facilitates subunit folding by DSC, completing the Ig fold of the subunit’s pilin domain. The adhesin subunit (FimH, red) is depicted with an additional N-terminal lectin domain, which contains the receptor-binding site. Chaperone-subunit complexes then interact with the OM usher (FimD), which comprises a β-barrel channel domain, a plug domain, an N-terminal periplasmic domain (NTD), and two C terminal domains (CTD1 and CTD2). (a) In the resting usher, the plug domain occludes the channel pore and masks the CTDs. (b and c) The usher is activated by binding of a FimC-FimH chaperone-adhesin complex to the usher NTD. This results in displacement of the plug from the channel and handoff of FimC-FimH to the usher CTDs, freeing the NTD to recruit the next chaperone-subunit complex (FimC-FimG). (d) The newly recruited complex bound to the NTD is oriented perfectly to undergo DSE with the previously recruited complex bound to the CTDs, forming the first link in the pilus fiber. The newly incorporated chaperone-subunit is then handed over from the NTD to the CTDs. (e) Repeated rounds of this process result in assembly and secretion of the pilus fiber. Different steps along this pathway are targets for antipilus therapeutics. (i) Vaccination using a full-length or truncated adhesin subunit inhibits pilus-mediated bacterial adhesion and pathogenesis. (ii) Small-molecule receptor analogs occupy the pilus adhesin binding site, preventing pili from adhering to host receptors. (iii) Pilicides inhibit pilus assembly via different mechanisms, such as interfering with chaperone-subunit or subunit-subunit interactions, interfering with binding of chaperone-subunit complexes to the usher, or inhibiting proper folding of the usher in the bacterial OM. (iv) Coilicides inhibit uncoiling and recoiling of the pilus rod, thus impairing resilience of the fibers during fluid flow.

Citation: Psonis J, Thanassi D. 2019. Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili, EcoSal Plus 2019; doi:10.1128/ecosalplus.ESP-0033-2018
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