Bacterial Cell Division Machinery: An Insight for Development of New Antibacterial Agent

  • Rajni Khan
  • Shashikant RayEmail author


Antibiotic resistances against bacterial diseases encouraged the design of novel and specific target based drugs. Screening of antibacterial agents against a specific target is an important strategy to develop novel inhibitors. FtsZ is a GTPase which orchestrates bacterial cytokinesis. FtsZ polymerizes in the presence of GTP and forms a contractile Z-ring at the mid of the bacterial cell which determines the plane of cell division. FtsZ assembly is highly dynamic in nature and it is tightly regulated by its interacting proteins known as regulators of FtsZ assembly. Some of these regulators promote the assembly of FtsZ protofilaments and stabilize the preformed protofilaments which lead to the formation of the divisome machinery complex known as positive regulators of FtsZ assembly. Contrary to the positive regulators, the negative regulators of the Z-ring assembly inhibit the formation of FtsZ protofilaments or destabilize the preformed protofilaments. The combined effect of both positive and negative regulators affects the localization of Z-ring during the bacterial cell division. FtsZ is a homologue of eukaryotic cytoskeleton protein tubulin, which is already used in cancer chemotherapy. Hence, the analysis of the mechanism of FtsZ assembly and exploring the interaction with its interacting proteins can help in designing FtsZ target based novel inhibitors.


Bacterial cell division Positive regulator Z-ring FtsZ assembly Divisome 



S.R. acknowledges Indian Institute of Technology Bombay, India and Mahatma Gandhi Central University, Motihari, Bihar. S. R also sincerely thanks to Ankit Rai for critical reading of the manuscript.


  1. Adams DW, Errington J. Bacterial cell division: assembly, maintenance and disassembly of the Z ring. Nat Rev Microbiol. 2009;7:642–53. Scholar
  2. Araujo-Bazan L, Ruiz-Avila LB, Andreu D, Huecas S, Andreu JM. Cytological profile of antibacterial FtsZ inhibitors and synthetic peptide MciZ. Front Microbiol. 2016;7:1558. Scholar
  3. Beall B, Lutkenhaus J. Impaired cell division and sporulation of a Bacillus subtilis strain with the ftsA gene deleted. J Bacteriol. 1992;174:2398–403.CrossRefGoogle Scholar
  4. Beuria TK, Krishnakumar SS, Sahar S, Singh N, Gupta K, Meshram M, Panda D. Glutamate-induced assembly of bacterial cell division protein FtsZ. J Biol Chem. 2003;278:3735–41. Scholar
  5. Beuria TK, Santra MK, Panda D. Sanguinarine blocks cytokinesis in bacteria by inhibiting FtsZ assembly and bundling. Biochemistry. 2005;44:16584–93. Scholar
  6. Beuria TK, Singh P, Surolia A, Panda D. Promoting assembly and bundling of FtsZ as a strategy to inhibit bacterial cell division: a new approach for developing novel antibacterial drugs. Biochem J. 2009;423:61–9. Scholar
  7. Bhattacharya A, Jindal B, Singh P, Datta A, Panda D. Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly – a mechanistic study of its antibacterial activity. FEBS J. 2013;280:4585–99. Scholar
  8. Bhattacharya A, Ray S, Singh D, Dhaked HP, Panda D. ZapC promotes assembly and stability of FtsZ filaments by binding at a different site on FtsZ than ZipA. Int J Biol Macromol. 2015;81:435–42. Scholar
  9. Bhattacharya D, Kumar A, Panda D. WhmD promotes the assembly of Mycobacterium smegmatis FtsZ: a possible role of WhmD in bacterial cell division. Int J Biol Macromol. 2017;95:582–91. Scholar
  10. Boberek JM, Stach J, Good L. Genetic evidence for inhibition of bacterial division protein FtsZ by berberine. PLoS One. 2010;5:e13745. Scholar
  11. Bork P, Sander C, Valencia A. An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins. Proc Natl Acad Sci U S A. 1992;89:7290–4.CrossRefGoogle Scholar
  12. Boyd D, Nixon R, Gillespie S, Gillespie D. Screening of Escherichia coli temperature-sensitive mutants by pretreatment with glucose starvation. J Bacteriol. 1968;95:1040–50.PubMedPubMedCentralGoogle Scholar
  13. Buczek MS, Cardenas Arevalo AL, Janakiraman A. ClpXP and ClpAP control the Escherichia coli division protein ZapC by proteolysis. Microbiology. 2016;162:909–20. Scholar
  14. Buddelmeijer N, Beckwith J. Assembly of cell division proteins at the E. coli cell center. Curr Opin Microbiol. 2002;5:553–7.CrossRefGoogle Scholar
  15. Buske PJ, Levin PA. Extreme C terminus of bacterial cytoskeletal protein FtsZ plays fundamental role in assembly independent of modulatory proteins. J Biol Chem. 2012;287:10945–57. Scholar
  16. Cabeen MT, Jacobs-Wagner C. The bacterial cytoskeleton. Annu Rev Genet. 2010;44:365–92. Scholar
  17. Camberg JL, Hoskins JR, Wickner S. ClpXP protease degrades the cytoskeletal protein, FtsZ, and modulates FtsZ polymer dynamics. Proc Natl Acad Sci U S A. 2009;106:10614–9. Scholar
  18. Changes in the oligomerization potential of the division inhibitor UgtP co-ordinate Bacillus subtilis cell size with nutrient availability. Mol Microbiol. 2012;86:594–610. Scholar
  19. Clement MJ, et al. The stathmin-derived I19L peptide interacts with FtsZ and alters its bundling. Biochemistry. 2009;48:9734–44. Scholar
  20. Dai K, Lutkenhaus J. The proper ratio of FtsZ to FtsA is required for cell division to occur in Escherichia coli. J Bacteriol. 1992;174:6145–51.CrossRefGoogle Scholar
  21. Dai K, Mukherjee A, Xu Y, Lutkenhaus J. Mutations in ftsZ that confer resistance to SulA affect the interaction of FtsZ with GTP. J Bacteriol. 1994;176:130–6.CrossRefGoogle Scholar
  22. Dassain M, Bouche JP. The min locus, which confers topological specificity to cell division, is not involved in its coupling with nucleoid separation. J Bacteriol. 1994;176:6143–5.CrossRefGoogle Scholar
  23. DeLano WL. The PyMOL molecular genetics graphics system. San Carlos: DeLano Scientific LLC; 2002.Google Scholar
  24. Din N, Quardokus EM, Sackett MJ, Brun YV. Dominant C-terminal deletions of FtsZ that affect its ability to localize in caulobacter and its interaction with FtsA. Mol Microbiol. 1998;27:1051–63.CrossRefGoogle Scholar
  25. Durand-Heredia JM, Yu HH, De Carlo S, Lesser CF, Janakiraman A. Identification and characterization of ZapC, a stabilizer of the FtsZ ring in Escherichia coli. J Bacteriol. 2011;193:1405–13. Scholar
  26. Durand-Heredia J, Rivkin E, Fan G, Morales J, Janakiraman A. Identification of ZapD as a cell division factor that promotes the assembly of FtsZ in Escherichia coli. J Bacteriol. 2012;194:3189–98. Scholar
  27. Ebersbach G, Galli E, Moller-Jensen J, Lowe J, Gerdes K. Novel coiled-coil cell division factor ZapB stimulates Z ring assembly and cell division. Mol Microbiol. 2008;68:720–35. Scholar
  28. Erickson HP, Anderson DE, Osawa M. FtsZ in bacterial cytokinesis: cytoskeleton and force generator all in one. Microbiol Mol Biol Rev. 2010;74:504–28. Scholar
  29. Errington J, Daniel RA, Scheffers DJ. Cytokinesis in bacteria. Microbiol Mol Biol Rev. 2003;67:52–65, table of contentsCrossRefGoogle Scholar
  30. Fernandez De Henestrosa AR, Ogi T, Aoyagi S, Chafin D, Hayes JJ, Ohmori H, Woodgate R. Identification of additional genes belonging to the LexA regulon in Escherichia coli. Mol Microbiol. 2000;35:1560–72.CrossRefGoogle Scholar
  31. Feucht A, Lucet I, Yudkin MD, Errington J. Cytological and biochemical characterization of the FtsA cell division protein of Bacillus subtilis. Mol Microbiol. 2001;40:115–25.CrossRefGoogle Scholar
  32. Goehring NW, Beckwith J. Diverse paths to midcell: assembly of the bacterial cell division machinery. Curr Biol. 2005;15:R514–26. Scholar
  33. Gola S, Munder T, Casonato S, Manganelli R, Vicente M. The essential role of SepF in mycobacterial division. Mol Microbiol. 2015;97:560–76. Scholar
  34. Gomez JE, Bishai WR. whmD is an essential mycobacterial gene required for proper septation and cell division. Proc Natl Acad Sci USA. 2000;97:8554–9. Scholar
  35. Gueiros-Filho FJ, Losick R. A widely conserved bacterial cell division protein that promotes assembly of the tubulin-like protein FtsZ. Genes Dev. 2002;16:2544–56. Scholar
  36. Haeusser DP, Schwartz RL, Smith AM, Oates ME, Levin PA. EzrA prevents aberrant cell division by modulating assembly of the cytoskeletal protein FtsZ. Mol Microbiol. 2004;52:801–14. Scholar
  37. Hale CA, de Boer PA. Recruitment of ZipA to the septal ring of Escherichia coli is dependent on FtsZ and independent of FtsA. J Bacteriol. 1999;181:167–76.PubMedPubMedCentralGoogle Scholar
  38. Hale CA, Shiomi D, Liu B, Bernhardt TG, Margolin W, Niki H, de Boer PA. Identification of Escherichia coli ZapC (YcbW) as a component of the division apparatus that binds and bundles FtsZ polymers. J Bacteriol. 2011;193:1393–404. Scholar
  39. Handler AA, Lim JE, Losick R. Peptide inhibitor of cytokinesis during sporulation in Bacillus subtilis. Mol Microbiol. 2008;68:588–99. Scholar
  40. Harry E, Monahan L, Thompson L. Bacterial cell division: the mechanism and its precison. Int Rev Cytol. 2006;253:27–94. Scholar
  41. Haydon DJ, et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science. 2008;321:1673–5. Scholar
  42. Hu Z, Mukherjee A, Pichoff S, Lutkenhaus J. The MinC component of the division site selection system in Escherichia coli interacts with FtsZ to prevent polymerization. Proc Natl Acad Sci U S A. 1999;96:14819–24.CrossRefGoogle Scholar
  43. Huang J, Cao C, Lutkenhaus J. Interaction between FtsZ and inhibitors of cell division. J Bacteriol. 1996;178:5080–5.CrossRefGoogle Scholar
  44. Huang Q, et al. Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. J Med Chem. 2006;49:463–6. Scholar
  45. Huang KH, Mychack A, Tchorzewski L, Janakiraman A. Characterization of the FtsZ C-terminal variable (CTV) region in Z-ring assembly and interaction with the Z-ring stabilizer ZapD in E. coli cytokinesis. PLoS One. 2016;11:e0153337. Scholar
  46. Ishikawa S, Kawai Y, Hiramatsu K, Kuwano M, Ogasawara N. A new FtsZ-interacting protein, YlmF, complements the activity of FtsA during progression of cell division in Bacillus subtilis. Mol Microbiol. 2006;60:1364–80. Scholar
  47. Jaiswal R, Beuria TK, Mohan R, Mahajan SK, Panda D. Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ. Biochemistry. 2007;46:4211–20. Scholar
  48. Jindal B, Bhattacharya A, Panda D. Inhibitors of bacterial cell partitioning. In: Antibiotics- targets, mechanisms and resistance. Weinheim: Wiley-VCH; 2013. p. 151–82.CrossRefGoogle Scholar
  49. Kapoor S, Panda D. Targeting FtsZ for antibacterial therapy: a promising avenue. Expert Opin Ther Targets. 2009;13:1037–51. Scholar
  50. Keffer JL, Huecas S, Hammill JT, Wipf P, Andreu JM, Bewley CA. Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria. Bioorg Med Chem. 2013;21:5673–8. Scholar
  51. Krol E, van Kessel SP, van Bezouwen LS, Kumar N, Boekema EJ, Scheffers DJ. Bacillus subtilis SepF binds to the C-terminus of FtsZ. PLoS One. 2012;7:e43293. Scholar
  52. Kuchibhatla A, Bhattacharya A, Panda D. ZipA binds to FtsZ with high affinity and enhances the stability of FtsZ protofilaments. PLoS One. 2011;6:e28262. Scholar
  53. Kumar K, Awasthi D, Berger WT, Tonge PJ, Slayden RA, Ojima I. Discovery of anti-TB agents that target the cell-division protein FtsZ. Future Med Chem. 2010;2:1305–23. Scholar
  54. Land AD, Luo Q, Levin PA. Functional domain analysis of the cell division inhibitor EzrA. PLoS One. 2014;9:e102616. Scholar
  55. Lappchen T, Hartog AF, Pinas VA, Koomen GJ, den Blaauwen T. GTP analogue inhibits polymerization and GTPase activity of the bacterial protein FtsZ without affecting its eukaryotic homologue tubulin. Biochemistry. 2005;44:7879–84. Scholar
  56. Levin PA, Kurtser IG, Grossman AD. Identification and characterization of a negative regulator of FtsZ ring formation in Bacillus subtilis. Proc Natl Acad Sci U S A. 1999;96:9642–7.CrossRefGoogle Scholar
  57. Levin PA, Schwartz RL, Grossman AD. Polymer stability plays an important role in the positional regulation of FtsZ. J Bacteriol. 2001;183:5449–52.CrossRefGoogle Scholar
  58. Lock RL, Harry EJ. Cell-division inhibitors: new insights for future antibiotics. Nat Rev Drug Discov. 2008;7:324–38. Scholar
  59. Lowe J. Crystal structure determination of FtsZ from methanococcus jannaschii. J Struct Biol. 1998;124:235–43. Scholar
  60. Lowe J, Amos LA. Crystal structure of the bacterial cell-division protein FtsZ. Nature. 1998;391:203–6. Scholar
  61. Lowe J, Amos LA. Tubulin-like protofilaments in Ca2+-induced FtsZ sheets. EMBO J. 1999;18:2364–71. Scholar
  62. Ma X, Margolin W. Genetic and functional analyses of the conserved C-terminal core domain of Escherichia coli FtsZ. J Bacteriol. 1999;181:7531–44.PubMedPubMedCentralGoogle Scholar
  63. Ma X, Ehrhardt DW, Margolin W. Colocalization of cell division proteins FtsZ and FtsA to cytoskeletal structures in living Escherichia coli cells by using green fluorescent protein. Proc Natl Acad Sci U S A. 1996;93:12998–3003.CrossRefGoogle Scholar
  64. Mukherjee A, Lutkenhaus J. Guanine nucleotide-dependent assembly of FtsZ into filaments. J Bacteriol. 1994;176:2754–8.CrossRefGoogle Scholar
  65. Mukherjee A, Lutkenhaus J. Analysis of FtsZ assembly by light scattering and determination of the role of divalent metal cations. J Bacteriol. 1999;181:823–32.PubMedPubMedCentralGoogle Scholar
  66. Mukherjee A, Dai K, Lutkenhaus J. Escherichia coli cell division protein FtsZ is a guanine nucleotide binding protein. Proc Natl Acad Sci U S A. 1993;90:1053–7.CrossRefGoogle Scholar
  67. Nogales E. A structural view of microtubule dynamics. Cell Mol Life Sci. 1999;56:133–42.CrossRefGoogle Scholar
  68. Nogales E, Downing KH, Amos LA, Lowe J. Tubulin and FtsZ form a distinct family of GTPases. Nat Struct Biol. 1998;5:451–8.CrossRefGoogle Scholar
  69. Panda P, Taviti AC, Satpati S, Kar MM, Dixit A, Beuria TK. Doxorubicin inhibits E. coli division by interacting at a novel site in FtsZ. Biochem J. 2015;471:335–46. Scholar
  70. Pichoff S, Lutkenhaus J. Escherichia coli division inhibitor MinCD blocks septation by preventing Z-ring formation. J Bacteriol. 2001;183:6630–5. Scholar
  71. Pichoff S, Lutkenhaus J. Unique and overlapping roles for ZipA and FtsA in septal ring assembly in Escherichia coli. EMBO J. 2002;21:685–93.CrossRefGoogle Scholar
  72. Pichoff S, Lutkenhaus J. Tethering the Z ring to the membrane through a conserved membrane targeting sequence in FtsA. Mol Microbiol. 2005;55:1722–34. Scholar
  73. Pichoff S, Lutkenhaus J. Identification of a region of FtsA required for interaction with FtsZ. Mol Microbiol. 2007;64:1129–38. Scholar
  74. Possoz C, Newmark J, Sorto N, Sherratt DJ, Tolmasky ME. Sublethal concentrations of the aminoglycoside amikacin interfere with cell division without affecting chromosome dynamics. Antimicrob Agents Chemother. 2007;51:252–6. Scholar
  75. Rai D, Singh JK, Roy N, Panda D. Curcumin inhibits FtsZ assembly: an attractive mechanism for its antibacterial activity. Biochem J. 2008;410:147–55. Scholar
  76. Ramirez-Arcos S, et al. Conserved glycines in the C terminus of MinC proteins are implicated in their functionality as cell division inhibitors. J Bacteriol. 2004;186:2841–55.CrossRefGoogle Scholar
  77. Raskin DM, de Boer PA. Rapid pole-to-pole oscillation of a protein required for directing division to the middle of Escherichia coli. Proc Natl Acad Sci U S A. 1999;96:4971–6.CrossRefGoogle Scholar
  78. Ray S, Kumar A, Panda D. GTP regulates the interaction between MciZ and FtsZ: a possible role of MciZ in bacterial cell division. Biochemistry. 2013;52:392–401. Scholar
  79. Ray S, Dhaked HP, Panda D. Antimicrobial peptide CRAMP (16-33) stalls bacterial cytokinesis by inhibiting FtsZ assembly. Biochemistry. 2014;53:6426–9. Scholar
  80. Ray S, Jindal B, Kunal K, Surolia A, Panda D. BT-benzo-29 inhibits bacterial cell proliferation by perturbing FtsZ assembly. FEBS J. 2015;282:4015–33. Scholar
  81. RayChaudhuri D, Park JT. Escherichia coli cell-division gene ftsZ encodes a novel GTP-binding protein. Nature. 1992;359:251–4. Scholar
  82. Roach EJ, Wroblewski C, Seidel L, Berezuk AM, Brewer D, Kimber MS, Khursigara CM. Structure and mutational analyses of Escherichia coli ZapD reveal charged residues involved in FtsZ filament bundling. J Bacteriol. 2016;198:1683–93. Scholar
  83. Santra MK, Beuria TK, Banerjee A, Panda D. Ruthenium red-induced bundling of bacterial cell division protein, FtsZ. J Biol Chem. 2004;279:25959–65. Scholar
  84. Santra MK, Dasgupta D, Panda D. Deuterium oxide promotes assembly and bundling of FtsZ protofilaments. Proteins. 2005;61:1101–10. Scholar
  85. Scheffers D, Driessen AJ. The polymerization mechanism of the bacterial cell division protein FtsZ. FEBS Lett. 2001;506:6–10.CrossRefGoogle Scholar
  86. Shiomi D, Margolin W. The C-terminal domain of MinC inhibits assembly of the Z ring in Escherichia coli. J Bacteriol. 2007;189:236–43. Scholar
  87. Singh JK, Makde RD, Kumar V, Panda D. A membrane protein, EzrA, regulates assembly dynamics of FtsZ by interacting with the C-terminal tail of FtsZ. Biochemistry. 2007;46:11013–22. Scholar
  88. Singh JK, Makde RD, Kumar V, Panda D. SepF increases the assembly and bundling of FtsZ polymers and stabilizes FtsZ protofilaments by binding along its length. J Biol Chem. 2008;283:31116–24. Scholar
  89. Singh P, Jindal B, Surolia A, Panda D. A rhodanine derivative CCR-11 inhibits bacterial proliferation by inhibiting the assembly and GTPase activity of FtsZ. Biochemistry. 2012;51:5434–42. Scholar
  90. Singh D, Bhattacharya A, Rai A, Dhaked HP, Awasthi D, Ojima I, Panda D. SB-RA-2001 inhibits bacterial proliferation by targeting FtsZ assembly. Biochemistry. 2014;53:2979–92. Scholar
  91. Stricker J, Maddox P, Salmon ED, Erickson HP. Rapid assembly dynamics of the Escherichia coli FtsZ-ring demonstrated by fluorescence recovery after photobleaching. Proc Natl Acad Sci U S A. 2002;99:3171–5. Scholar
  92. Taviti AC, Beuria TK. MinD directly interacts with FtsZ at H10 helix suggests a model for robust activation of MinC to destabilize FtsZ polymers. Biochem J. 2017;474(18):3189–205. Scholar
  93. Trusca D, Scott S, Thompson C, Bramhill D. Bacterial SOS checkpoint protein SulA inhibits polymerization of purified FtsZ cell division protein. J Bacteriol. 1998;180:3946–53.PubMedPubMedCentralGoogle Scholar
  94. van den Ent F, Lowe J. Crystal structure of the cell division protein FtsA from Thermotoga maritima. EMBO J. 2000;19:5300–7. Scholar
  95. Wang X, Huang J, Mukherjee A, Cao C, Lutkenhaus J. Analysis of the interaction of FtsZ with itself, GTP, and FtsA. J Bacteriol. 1997;179:5551–9.CrossRefGoogle Scholar
  96. Wang J, et al. Discovery of a small molecule that inhibits cell division by blocking FtsZ, a novel therapeutic target of antibiotics. J Biol Chem. 2003;278:44424–8. Scholar
  97. Weart RB, Lee AH, Chien AC, Haeusser DP, Hill NS, Levin PA. A metabolic sensor governing cell size in bacteria. Cell. 2007;130:335–47. Scholar
  98. White EL, Suling WJ, Ross LJ, Seitz LE, Reynolds RC. 2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ. J Antimicrob Chemother. 2002;50:111–4.CrossRefGoogle Scholar
  99. Woldringh CL. The role of co-transcriptional translation and protein translocation (transertion) in bacterial chromosome segregation. Mol Microbiol. 2002;45:17–29.CrossRefGoogle Scholar
  100. Woldringh CL, Mulder E, Huls PG, Vischer N. Toporegulation of bacterial division according to the nucleoid occlusion model. Res Microbiol. 1991;142:309–20.CrossRefGoogle Scholar
  101. Wu LJ, Errington J. Coordination of cell division and chromosome segregation by a nucleoid occlusion protein in Bacillus subtilis. Cell. 2004;117:915–25. Scholar
  102. Zaritsky A, Woldringh CL. Localizing cell division in spherical Escherichia coli by nucleoid occlusion. FEMS Microbiol Lett. 2003;226:209–14.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of PhysiologyUniversity of CalcuttaKolkataIndia
  2. 2.Department of Biotechnology, School of Life SciencesMahatma Gandhi Central UniversityMotihariIndia

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