We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Identification of agents targeting FtsZ assembly

    Dulal Panda

    Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India

    ,
    Dipanwita Bhattacharya

    Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India

    ,
    Quanqing Helen Gao

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    ,
    Pratik M Oza

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    ,
    H-Y Jennifer Lin

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    ,
    Bryson Hawkins

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    ,
    David E Hibbs

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    &
    Paul W Groundwater

    *Author for correspondence:

    E-mail Address: paul.groundwater@sydney.edu.au

    Faculty of Pharmacy, Bank Building, Science Road, The University of Sydney, Sydney NSW 2006, Australia

    Published Online:https://doi.org/10.4155/fmc-2016-0041

    Filamenting temperature-sensitive mutant Z (FtsZ), an essential cell division protein in bacteria, has recently emerged as an important and exploitable antibacterial target. Cytokinesis in bacteria is regulated by the assembly dynamics of this protein, which is ubiquitously present in eubacteria. The perturbation of FtsZ assembly has been found to have a deleterious effect on the cytokinetic machinery and, in turn, upon cell survival. FtsZ is highly conserved among prokaryotes, offering the possibility of broad-spectrum antibacterial agents, while its limited sequence homology with tubulin (an essential protein in eukaryotic mitosis) offers the possibility of selective toxicity. This review aims to summarize current knowledge regarding the mechanism of action of FtsZ, and to highlight existing attempts toward the development of clinically useful inhibitors.

    Papers of special note have been highlighted as: •• of considerable interest

    References

    • 1 Margolin W. FtsZ and the division of prokaryotic cells and organelles. Nat. Rev. Mol. Cell Biol. 611, 862–871 (2005).
    • 2 Carballido-Lopez R, Errington J. A dynamic bacterial cytoskeleton. Trends Cell Biol. 13, 577–583 (2003). •• A review of the properties and roles of actin and Tubulin homologues in bacteria.
    • 3 Walker JR, Kovarik A, Allen JS, Gustafson RA. Regulation of bacterial cell-division – temperature-sensitive mutants of Escherichia coli that are defective in septum formation. J. Bacteriol. 123, 693–703 (1975).
    • 4 Hirota Y, Ryter A, Jacob F. Thermosensitive mutants of E. coli affected in processes of DNA synthesis and cellular division. Cold Spring Harb. Symp. Quant. Biol. 33, 677–693 (1968).
    • 5 Begg KJ, Donachie WD. Cell shape and division in Escherichia coli – experiments with shape and division mutants. J. Bacteriol. 163, 615–622 (1985). •• Describes the results from mutational studies which demonstrate that different fts genes control different stages in septation.
    • 6 Taschner PEM, Huls PG, Pas E, Woldringh CL. Division behaviour and shape changes in isogenic ftsZ, ftsQ, ftsA, pbpB and ftsE cell-division mutants of Escherichia coli during temperature shift experiments. J. Bacteriol. 170, 1533–1540 (1988).
    • 7 Erickson HP. FtsZ, a prokaryotic homolog of Tubulin? Cell 80, 367–370 (1995).
    • 8 Matsui T, Yamane J, Mogi N et al. Structural reorganization of the bacterial cell-division protein FtsZ from Staphylococcus aureus. Acta Crystallogr. D Biol. Crystallogr. 68, 1175–1188 (2012). •• Describes the conformational changes evident in the x-ray crystal structures of Staphylococcus aureus Filamenting temperature-sensitive mutant Z (FtsZ) in its apo, GDP-bound and inhibitor-complex forms.
    • 9 Lowe J, Li H, Downing KH, Nogales E. Refined structure of alpha beta-tubulin at 3.5 A resolution. J. Mol. Biol. 313, 1045–1057 (2001).
    • 10 Lowe J, Amos LA. Crystal structure of the bacterial cell-division protein FtsZ. Nature 391, 203–206 (1998). •• Describes the crystal structure of FtsZ from Methanococcus Jannaschii and the finding that GDP binding is different from that typically found in GTPases.
    • 11 Moreland JL, Gramada A, Buzko OV, Zhang Q, Bourne PE. The Molecular Biology Toolkit (MBT): a modular platform for developing molecular visualization applications. BMC Bioinform. 6, 21 (2005).
    • 12 Xu D, Zhang Y. Generating triangulated macromolecular surfaces by Euclidean distance transform. PLoS ONE 4, e8140 (2009).
    • 13 Nogales E, Downing KH, Amos LA, Löwe J. Tubulin and FtsZ form a distinct family of GTPases. Nat. Struct. Biol. 5, 451–458 (1998). •• A detailed comparison of the structures of FtsZ and Tubulin.
    • 14 Wang XD, Lutkenhaus J. The FtsZ protein of Bacillus subtilis is localized at the division site and has GTPase activity that is dependent upon FtsZ concentration. Mol. Microbiol. 9, 435–442 (1993).
    • 15 Li Z, Trimble MJ, Brun YV, Jensen GJ. The structure of FtsZ filaments in vivo suggests a force-generating role in cell division. EMBO J. 26, 4694–4708 (2007).
    • 16 Lutkenhaus J, Pichoff S, Du SS. Bacterial cytokinesis: from Z ring to divisome. Cytoskeleton 69, 778–790 (2012).
    • 17 Ramirez-Aportela E, Lopez-Blanco JR, Andreu JM et al. Understanding nucleotide-regulated FtsZ filament dynamics and the monomer assembly switch with large-scale atomistic simulations. Biophys. J. 107, 2164–2176 (2014).
    • 18 Mukherjee A, Lutkenhaus J. Dynamic assembly of FtsZ regulated by GTP hydrolysis. EMBO J. 17, 462–469 (1998).
    • 19 Anderson DE, Gueiros-Filho FJ, Erickson HP. Assembly dynamics of FtsZ rings in Bacillus subtilis and Escherichia coli and effects of FtsZ-regulating proteins. J. Bacteriol. 186, 5775–5781 (2004).
    • 20 RSCB. www.rcsb.org.
    • 21 Mukherjee A, Dai K, Lutkenhaus J. Escherichia-coli cell-division protein FtsZ is a guanine-nucleotide binding-protein. Proc. Natl Acad. Sci. USA 90, 1053–1057 (1993).
    • 22 de Boer P, Crossley R, Rothfield L. The essential bacterial cell-division protein FtsZ is a GTPase. Nature 359, 254–256 (1992). •• The discovery that GTP binding and hydrolysis by FtsZ are important steps in bacterial cytokinesis.
    • 23 Lowe J. Crystal structure determination of FtsZ from Methanococcus jannaschii. J. Struct. Biol. 124, 235–243 (1998).
    • 24 de Pereda JM, Leynadier D, Evangelio JA, Chacon P, Andreu JM. Tubulin secondary structure analysis, limited proteolysis sites, and homology to FtsZ. Biochemistry 35, 14203–14215 (1996).
    • 25 Rossmann MG, Moras D, Olsen KW. Chemical and biological evolution of nucleotide-binding protein. Nature 250, 194–199 (1974).
    • 26 Desai A, Mitchison TJ. Tubulin and FtsZ structures: functional and therapeutic implications. Bioessays 20, 523–527 (1998).
    • 27 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. 176, 130–136 (1994).
    • 28 Scheffers DJ, de Wit JG, den Blaauwen T, Driessen AJM. GTP hydrolysis of cell division protein FtsZ: evidence that the active site is formed by the association of monomers. Biochemistry 41, 521–529 (2002).
    • 29 Shin JY, Vollmer W, Lagos R, Monasterio O. Glutamate 83 and arginine 85 of helix H3 bend are key residues for FtsZ polymerization, GTPase activity and cellular viability of Escherichia coli: lateral mutations affect FtsZ polymerization and E. coli viability. BMC Microbiol. 13, 26 (2013).
    • 30 Bramhill D, Thompson CM. GTP-dependent polymerization of Escherichia coli FtsZ protein to form Tubules. Proc. Natl Acad. Sci. USA 91, 5813–5817 (1994).
    • 31 Lu C, Reedy M, Erickson HP. Straight and curved conformations of FtsZ are regulated by GTP hydrolysis. J. Bacteriol. 182, 164–170 (2000).
    • 32 Ryan KR, Shapiro L. Temporal and spatial regulation in prokaryotic cell cycle progression and development. Annu. Rev. Biochem. 72, 367–394 (2003).
    • 33 Mukherjee A, Saez C, Lutkenhaus J. Assembly of an FtsZ mutant deficient in GTPase activity has implications for FtsZ assembly and the role of the Z ring in cell division. J. Bacteriol. 183, 7190–7197 (2001).
    • 34 Oliva MA, Trambaiolo D, Lowe J. Structural insights into the conformational variability of FtsZ. J. Mol. Biol. 373, 1229–1242 (2007).
    • 35 Coan KED, Maltby DA, Burlingame AL et al. Promiscuous aggregate-based inhibitors promote enzyme unfolding. J. Med. Chem. 52, 2067–2075 (2009).
    • 36 Harry E, Monahan L, Thompson L. Bacterial cell division: the mechanism and its precison. Intnl. Rev. Cytology 253, 27–94 (2006).
    • 37 Romberg L, Mitchison TJ. Rate-limiting guanosine 5′-triphosphate hydrolysis during nucleotide turnover by FtsZ, a prokaryotic Tubulin homologue involved in bacterial cell division. Biochemistry 43, 282–288 (2004).
    • 38 Coue M, Lombillo VA, McIntosh JR. Microtubule depolymerization promotes particle and chromosome movement In vitro. J. Cell Biol. 112, 1165–1175 (1991).
    • 39 Osawa M, Anderson DE, Erickson HP. Reconstitution of contractile FtsZ rings in liposomes. Science 320, 792–794 (2008).
    • 40 Elsen NL, Lu J, Parthasarathy G et al. Mechanism of action of the cell-division inhibitor PC190723: modulation of FtsZ assembly cooperativity. J. Amer. Chem. Soc. 134, 12342–12345 (2012).
    • 41 Tan CM, Therien AG, Lu J et al. Restoring methicillin-resistant Staphylococcus aureus susceptibility to beta-lactam antibiotics. Sci. Transl. Med. 4, 126ra135 (2012).
    • 42 Mosyak L, Zhang Y, Glasfeld E et al. The bacterial cell-division protein ZipA and its interaction with an FtsZ fragment revealed by x-ray crystallography. EMBO J. 19, 3179–3191 (2000).
    • 43 Hamoen LW, Meile JC, de Jong W, Noirot P, Errington J. SepF, a novel FtsZ-interacting protein required for a late step in cell division. Mol. Microbiol. 59, 989–999 (2006).
    • 44 Pichoff S, Lutkenhaus J. Unique and overlapping roles for ZipA and FtsA in septal ring assembly in Escherichia coli. EMBO J. 21, 685–693 (2002).
    • 45 Hale CA, de Boer PAJ. Recruitment of ZipA to the septal ring of Escherichia coli is dependent on FtsZ and independent of FtsA. J. Bacteriol. 181, 167–176 (1999).
    • 46 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. 283, 31116–31124 (2008).
    • 47 Mohammadi T, Ploeger GEJ, Verheul J et al. The GTPase activity of Escherichia coli FtsZ determines the magnitude of the FtsZ polymer bundling by ZapA in vitro. Biochemistry 48, 11056–11066 (2009).
    • 48 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. 68, 720–735 (2008).
    • 49 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. 193, 1405–1413 (2011).
    • 50 Durand-Heredia J, Rivkin E, Fan GX, Morales J, Janakiraman A. Identification of ZapD as a cell division factor that promotes the assembly of FtsZ in Escherichia coli. J. Bacteriol. 194, 3189–3198 (2012).
    • 51 Weart RB, Lee AH, Chien AC, Haeusser DP, Hill NS, Levin PA. A metabolic sensor governing cell size in bacteria. Cell 130, 335–347 (2007).
    • 52 Handler AA, Lim JE, Losick R. Peptide inhibitor of cytokinesis during sporulation in Bacillus subtilis. Mol. Microbiol. 68, 588–599 (2008).
    • 53 Cordell SC, Robinson EJH, Lowe J. Crystal structure of the SOS cell division inhibitor SulA and in complex with FtsZ. Proc. Natl Acad. Sci. USA 100, 7889–7894 (2003).
    • 54 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. 52, 801–814 (2004).
    • 55 Pichoff S, Lutkenhaus J. Escherichia coli division inhibitor MinCD blocks septation by preventing Z-ring formation. J. Bacteriol. 183, 6630–6635 (2001).
    • 56 Bramkamp M, Emmins R, Weston L, Donovan C, Daniel RA, Errington J. A novel component of the division-site selection system of Bacillus subtilis and a new mode of action for the division inhibitor MinCD. Mol. Microbiol. 70, 1556–1569 (2008).
    • 57 Pinho MG, Kjos M, Veening J-W. How to get (a)round: mechanisms controlling growth and division of coccoid bacteria. Nat. Rev. Microbiol. 11, 601–614 (2013).
    • 58 Lutkenhaus J. Assembly dynamics of the bacterial MinCDE system and spatial regulation of the Z ring. Ann. Rev. Biochem. 76, 539–562 (2007).
    • 59 Wu LJ, Ishikawa S, Kawai Y, Oshima T, Ogasawara N, Errington J. Noc protein binds to specific DNA sequences to coordinate cell division with chromosome segregation. EMBO J. 28, 1940–1952 (2009).
    • 60 Foss MH, Eun YJ, Grove CI et al. Inhibitors of bacterial Tubulin target bacterial membranes in vivo. MedChemComm 4, 112–119 (2013).
    • 61 FT Map. http://ftmap.bu.edu/.
    • 62 Kozakov D, Hall DR, Napoleon RL, Yueh C, Whitty A, Vajda S. New frontiers in druggability. J. Med. Chem. 58, 9063–9088 (2015).
    • 63 Stokes NR, Sievers J, Barker S et al. Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. J. Biol. Chem. 280, 39709–39715 (2005).
    • 64 Haydon DJ, Stokes NR, Ure R et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321, 1673–1675 (2008). •• The report of the potent and selective bactericidal activity of PC190723 as a result of its inhibition of FtsZ and prevention of cell division.
    • 65 Andreu JM, Schaffner-Barbero C, Huecas S et al. The antibacterial cell division inhibitor PC190723 is an FtsZ polymer-stabilizing agent that induces filament assembly and condensation. J. Biol. Chem. 285, 14239–14246 (2010).
    • 66 Singh D, Bhattacharya A, Rai A et al. SB-RA-2001 inhibits bacterial proliferation by targeting FtsZ assembly. Biochemistry 53, 2979–2992 (2014).
    • 67 Ray S, Jindal B, Kunal K, Surolia A, Panda D. BT-benzo-29 inhibits bacterial cell proliferation by perturbing FtsZ assembly. FEBS J. 282, 4015–4033 (2015).
    • 68 Anderson DE, Kim MB, Moore JT et al. Comparison of small molecule inhibitors of the bacterial cell division protein FtsZ and identification of a reliable cross-species inhibitor. ACS Chem. Biol. 7, 1918–1928 (2012). •• A comparison of the biochemical properties of reported FtsZ inhibitors.
    • 69 Ruiz-Ayila LB, Huecas S, Artola M et al. Synthetic inhibitors of bacterial cell division targeting the GTP-binding site of FtsZ. ACS Chem. Biol. 8, 2072–2083 (2013).
    • 70 Kaul M, Mark L, Zhang YZ, Parhi AK, LaVoie EJ, Pilch DS. An FtsZ-targeting prodrug with oral antistaphylococcal efficacy in vivo. Antimicrob. Agents Chemother. 57, 5860–5869 (2013).
    • 71 Margalit DN, Romberg L, Mets RB et al. Targeting cell division: small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality. Proc. Natl Acad. Sci. USA 101, 11821–11826 (2004).
    • 72 Plaza A, Keffer JL, Bifulco G, Lloyd JR, Bewley CA. Chrysophaentins A-H, antibacterial bisdiarylbutene macrocycles that inhibit the bacterial cell division protein FtsZ. J. Amer. Chem. Soc. 132, 9069 (2010).
    • 73 Li X, Sheng JZ, Huang GH et al. Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ. Eur. J. Med. Chem. 96, 32–41 (2015).
    • 74 Duggirala S, Nankar RP, Rajendran S, Doble M. Phytochemicals as inhibitors of bacterial cell division protein FtsZ: coumarins are promising candidates. Appl. Biochem. Biotechnol. 174, 283–296 (2014).
    • 75 Chiang CC, Cheng MJ, Peng CF, Huang HY, Chen IS. A novel dimeric coumarin analog and antimycobacterial constituents from Fatoua pilosa. Chem. Biodiversity 7, 1728–1736 (2010).
    • 76 Sun N, Chan FY, Lu YJ et al. Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity. PLoS ONE 9, e97514 (2014).
    • 77 Miguel A, Hsin J, Liu TY, Tang G, Altman RB, Huang KC. Variations in the binding pocket of an inhibitor of the bacterial division protein FtsZ across genotypes and species. PLoS Comput. Biol. 11, e1004117 (2015).
    • 78 Kaul M, Zhang YZ, Parhi AK et al. Enterococcal and streptococcal resistance to PC190723 and related compounds: molecular insights from a FtsZ mutational analysis. Biochimie 95, 1880–1887 (2013).
    • 79 Kaul M, Mark L, Zhang YZ, Parhi AK, LaVoie EJ, Pilch DS. Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723. Biochem. Pharmacol. 86, 1699–1707 (2013).
    • 80 Kaul M, Zhang YZ, Parhi AK, LaVoie EJ, Pilch DS. Inhibition of RND-type efflux pumps confers the FtsZ-directed prodrug TXY436 with activity against Gram-negative bacteria. Biochem. Pharmacol. 89, 321–328 (2014).
    • 81 Kaul M, Mark L, Zhang YZ et al. TXA709, an FtsZ-targeting benzamide prodrug with improved pharmacokinetics and enhanced in vivo efficacy against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 59, 4845–4855 (2015).
    • 82 Stokes NR, Baker N, Bennett JM et al. An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy. Antimicrob. Agents Chemother. 57, 317–325 (2013).
    • 83 Stokes NR, Baker N, Bennett JM et al. Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ. Bioorg. Med. Chem. Lett. 24, 353–359 (2014).
    • 84 Chiodini G, Pallavicini M, Zanotto C et al. Benzodioxane-benzamides as new bacterial cell division inhibitors. Eur. J. Med. Chem. 89, 252–265 (2015).
    • 85 Sarcina M, Mullineaux CW. Effects of Tubulin assembly inhibitors on cell division in prokaryotes in vivo. FEMS Microbiol. Lett. 191, 25–29 (2000).
    • 86 White EL, Suling WJ, Ross LJ, Seitz LE, Reynolds RC. 2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ. J. Antimicrob. Chemother. 50, 111–114 (2002).
    • 87 Reynolds RC, Srivastava S, Ross LJ, Suling WJ, White EL. A new 2-carbamoyl pteridine that inhibits mycobacterial FtsZ. Bioorg. Med. Chem. Lett. 14, 3161–3164 (2004).
    • 88 Kumar K, Awasthi D, Lee SY et al. Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class of antitubercular agents. J. Med. Chem. 54(1), 374–381 (2011).
    • 89 Knudson SE, Awasthi D, Kumar K et al. A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis. PLoS ONE 9, e93953 (2014).
    • 90 Awasthi D, Kumar K, Knudson SE, Slayden RA, Ojima I. SAR studies on trisubstituted benzimidazoles as inhibitors of Mtb FtsZ for the development of novel antitubercular agents. J. Med. Chem. 56, 9756–9770 (2013).
    • 91 Ojima I, Kumar K, Awasthi D, Vineberg JG. Drug discovery targeting cell division proteins, microtubules and FtsZ. Bioorg. Med. Chem. 22, 5060–5077 (2014).
    • 92 Mikuni S, Kodama K, Sasaki A et al. Screening for FtsZ dimerization inhibitors using fluorescence cross-correlation spectroscopy and surface resonance plasmon analysis. PLoS ONE 10, e130933 (2015).
    • 93 Lin Y, Zhu NY, Han YX, Jiang JD, Si SY. Identification of anti-tuberculosis agents that target the cell-division protein FtsZ. J. Antibiot. 67, 671–676 (2014).
    • 94 Chan F-Y, Sun N, Neves MAC et al. Identification of a new class of FtsZ inhibitors by structure-based design and in vitro screening. J. Chem. Inform. Mod. 53, 2131–2140 (2013).
    • 95 Haraguchi H, Oike S, Muroi H, Kubo I. Mode of antibacterial action of totarol, a diterpene from Podocarpus nagi. Planta Med. 62, 122–125 (1996).
    • 96 Jaiswal R, Beuria TK, Mohan R, Mahajan SK, Panda D. Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ. Biochemistry 46, 4211–4220 (2007).
    • 97 Chan FY, Sun N, Leung YC, Wong KY. Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with beta-lactam antibiotics. J. Antibiot. 68, 253–258 (2015).
    • 98 Nepomuceno GM, Chan KM, Huynh V et al. Synthesis and evaluation of quinazolines as inhibitors of the bacterial cell division protein FtsZ. ACS Med. Chem. Lett. 6, 308–312 (2015).
    • 99 Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature 277, 665–667 (1979).
    • 100 Huang Q, Kirikae F, Kirikae T et al. Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. J. Med. Chem. 49, 463–466 (2006).
    • 101 Kumar K, Awasthi D, Berger WT, Tonge PJ, Slayden RA, Ojima I. Discovery of anti-TB agents that target the cell-division protein FtsZ. Fut. Med. Chem. 2, 1305–1323 (2010).
    • 102 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. 21, 5673–5678 (2013).
    • 103 Domadia P, Swarup S, Bhunia A, Sivaraman J, Dasgupta D. Inhibition of bacterial cell division protein FtsZ by cinnamaldehyde. Biochem. Pharmacol. 74, 831–840 (2007).
    • 104 Chang S-T, Chang S-C, Chen P-F. Antibacterial activity of leaf essential oils and their constituents from Cinnamomum osmophloeum. J. Ethnopharmacol. 77, 123–127 (2001).
    • 105 Li X, Sheng J, Huang G et al. Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ. Eur. J. Med. Chem. 97, 32–41 (2015).
    • 106 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. 471, 335–346 (2015).
    • 107 Swift LP, Rephaeli A, Nudelman A et al. Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 66, 4863–4871 (2006).
    • 108 Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim. Biophys. Acta 1845, 84–89 (2014).
    • 109 White EL, Ross LJ, Reynolds RC, Seitz LE, Moore GD, Borhani DW. Slow polymerization of Mycobacterium tuberculosis FtsZ. J. Bacteriol. 182, 4028–4034 (2000).
    • 110 Sun J, Li MH, Wang XY et al. Vanillin derivatives as the selective small molecule inhibitors of FtsZ. Med. Chem. Res. 23, 2985–2994 (2014).
    • 111 Domadia PN, Bhunia A, Sivaraman J, Swarup S, Dasgupta D. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry 47, 3225–3234 (2008).
    • 112 Park HC, Gedi V, Cho JH et al. Characterization and In vitro inhibition studies of Bacillus anthracis FtsZ: a potential antibacterial target. Appl. Biochem. Biotechnol. 172, 3263–3270 (2014).
    • 113 Kelley C, Zhang YZ, Parhi A, Kaul M, Pilch DS, LaVoie EJ. 3-Phenyl substituted 6,7-dimethoxyisoquinoline derivatives as FtsZ-targeting antibacterial agents. Bioorg. Med. Chem. 20, 7012–7029 (2012).
    • 114 Zhang YZ, Giurleo D, Parhi A, Kaul M, Pilch DS, LaVoie EJ. Substituted 1,6-diphenylnaphthalenes as FtsZ-targeting antibacterial agents. Bioorg. Med. Chem. Lett. 23, 2001–2006 (2013).
    • 115 Parhi A, Lu SF, Kelley C, Kaul M, Pilch DS, LaVoie EJ. Antibacterial activity of substituted dibenzo[a,g]quinolizin-7-ium derivatives. Bioorg. Med. Chem. Lett. 22, 6962–6966 (2012).
    • 116 Parhi AK, Zhang YZ, Saionz KW et al. Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines. Bioorg. Med. Chem. Lett. 23, 4968–4974 (2013).
    • 117 Krol E, Borges AD, da Silva I et al. Antibacterial activity of alkyl gallates is a combination of direct targeting of FtsZ and permeabilization of bacterial membranes. Front. Microbiol. 6, 390 (2015).
    • 118 Artola M, Ruiz-Avila LB, Vergonos A et al. Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action. ACS Chem. Biol. 10, 834–843 (2015).
    • 119 Huecas S, Marcelo F, Perona A et al. Beyond a fluorescent probe: inhibition of cell division protein FtsZ by mant-GTP elucidated by NMR and biochemical approaches. ACS Chem. Biol. 10, 2382–2392 (2015).
    • 120 Läppchen T, Koomen GJ, Pinas V, Blaauwen dT, Hartog AF. GTP analogue inhibits polymerization and GTPase activity of the bacterial protein FtsZ without affecting its eukaryotic homologue Tubulin. Biochemistry 44, 7879–7884 (2005).
    • 121 Läppchen T, Pinas VA, Hartog AF et al. Probing FtsZ and Tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites. Chem. Biol. 15, 189–199 (2008).
    • 122 Schaffner-Barbero C, Martín-Fontecha M, Chacón P, Andreu JM. Targeting the assembly of bacterial cell division protein FtsZ with small molecules. ACS Chem. Biol. 7, 269 (2012).
    • 123 Marcelo F, Huecas S, Ruiz-Avila LB et al. Interactions of bacterial cell division protein FtsZ with C8-substituted guanine nucleotide inhibitors. A combined NMR, biochemical and molecular modeling perspective. J. Amer. Chem. Soc. 135, 16418–16428 (2013).
    • 124 Sorto NA, Painter PP, Fettinger JC, Tantillo DJ, Shaw JT. Design and synthesis of mimics of the T7-loop of FtsZ. Org. Lett. 15, 2700–2703 (2013).
    • 125 Pieraccini S, Rendine S, Jobichen C et al. Computer aided design of FtsZ targeting oligopeptides. RSC Adv. 3, 1739–1743 (2013).
    • 126 Rosenberger CM, Gallo RL, Finlay BB. Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication. Proc. Natl Acad. Sci. USA 101, 2422–2427 (2004).
    • 127 Ray S, Dhaked HP, Panda D. Antimicrobial peptide CRAMP (16–33) stalls bacterial cytokinesis by inhibiting FtsZ assembly. Biochemistry 53, 6426–6429 (2014).
    • 128 Ghosal A, Nielsen PE. Potent antibacterial antisense peptide-peptide nucleic acid conjugates against Pseudomonas aeruginosa. Nucl. Acid Ther. 22, 323–334 (2012).
    • 129 Meng JR, Da F, Ma X et al. Antisense growth inhibition of methicillin-resistant Staphylococcus aureus by locked nucleic acid conjugated with cell-penetrating peptide as a novel FtsZ inhibitor. Antimicrob. Agents Chemother. 59, 914–922 (2015).