Key Points
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Bacterial cell division is an essential process that is not yet targeted by clinically approved antibacterials. However, it is an area of untapped potential, with antibacterial discovery efforts now well underway.
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The septation process is driven by at least 12 proteins that are recruited to the division site at midcell to form the division machinery known as the divisome.
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Several features of the bacterial cell-division proteins would make them good candidate antibacterial targets, including their essentiality, their conservation in a wide range of bacterial pathogens, and, for the membrane-bound proteins, the absence of homologues in eukaryotes, and their accessibility to inhibitory compounds by virtue of their external location.
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The earliest event in bacterial cell division is the recruitment of a tubulin-like protein, FtsZ, to the division site to form a Z ring.
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Many inhibitors of FtsZ have been identified using various approaches. Although all have been shown to inhibit FtsZ in vitro, and most have antibacterial activity, there is usually little or no evidence for their antibacterial activity being due to FtsZ inhibition. In this respect PC58538/PC170942 and viriditoxin are the most promising candidates.
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For many divisome proteins catalytic activity has not been identified, and it is the protein–protein interactions that play a key role in the assembly of the divisome and the division process. These interactions may prove attractive for targeting. The ZipA–FtsZ interaction has been the subject of antibacterial discovery with no promising leads as yet.
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Significant progress in the discovery and development of small-molecule inhibitors of protein–protein interactions has been made through a number of different strategies. A general strategy for targeting protein interfaces, which is likely to emerge in the future, could be used to inhibit the plethora of protein–protein interactions that occur in bacterial cell division, such as the well-conserved DivIB–DivIC–FtsL interaction.
Abstract
The growing problem of antibiotic resistance has been exacerbated by the use of new drugs that are merely variants of older overused antibiotics. While it is naive to expect to restrain the spread of resistance without controlling antibacterial usage, the desperate need for drugs with novel targets has been recognized by health organizations, industry and academia alike. The wealth of knowledge available about the bacterial cell-division pathway has aided target-driven approaches to identify novel inhibitors. Here, we discuss the therapeutic potential of inhibiting bacterial cell division, and review the progress made in this exciting new area of antibacterial discovery.
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References
Leeb, M. Antibiotics: a shot in the arm. Nature 431, 892–893 (2004).
Jacobs, M. R. Retapamulin: a semisynthetic pleuromutilin compound for topical treatment of skin infections in adults and children. Future Microbiol. 2, 591–600 (2007).
DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185 (2003).
Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. Drug Discov. 6, 29–40 (2007).
Projan, S. J. & Youngman, P. J. Antimicrobials: new solutions badly needed. Curr. Opin. Microbiol. 5, 463–465 (2002).
Walsh, C. Where will new antibiotics come from? Nature Rev. Microbiol. 1, 65–70 (2003).
Rosamond, J. & Allsop, A. Harnessing the power of the genome in the search for new antibiotics. Science 287, 1973–1976 (2000).
Errington, J. Dynamic proteins and a cytoskeleton in bacteria. Nature Cell Biol. 5, 175–178 (2003).
Freiberg, C. & Brotz-Oesterhelt, H. Functional genomics in antibacterial drug discovery. Drug Discov. Today 10, 927–935 (2005).
Errington, J., Daniel, R. A. & Scheffers, D. J. Cytokinesis in bacteria. Microbiol. Mol. Biol. Rev. 67, 52–65 (2003).
Goehring, N. W. & Beckwith, J. Diverse paths to midcell: assembly of the bacterial cell division machinery. Curr. Biol. 15, R514–R526 (2005). A seminal review by key leaders in the bacterial cell division field. It presents an excellent and rigorous overview of cell division including a comparison of different species.
Harry, E., Monahan, L. & Thompson, L. Bacterial cell division: the mechanism and its precison. Int. Rev. Cytol. 253, 27–94 (2006). With reference 10, a recent comprehensive review of cell-division proteins in bacteria.
Vicente, M., Rico, A. I., Martinez-Arteaga, R. & Mingorance, J. Septum enlightenment: assembly of bacterial division proteins. J. Bacteriol. 188, 19–27 (2006).
Jensen, S. O., Thompson, L. S. & Harry, E. J. Cell division in Bacillus subtilis: FtsZ and FtsA association is Z-ring independent, and FtsA is required for efficient midcell Z-ring assembly. J. Bacteriol. 187, 6536–6544 (2005).
Pinho, M. G. & Errington, J. Dispersed mode of Staphylococcus aureus cell wall synthesis in the absence of the division machinery. Mol. Microbiol. 50, 871–881 (2003).
Buddelmeijer, N. & Beckwith, J. Assembly of cell division proteins at the E. coli cell center. Curr. Opin. Microbiol. 5, 553–557 (2002).
Chen, J. C. & Beckwith, J. FtsQ, FtsL and FtsI require FtsK, but not FtsN, for co-localization with FtsZ during Escherichia coli cell division. Mol. Microbiol. 42, 395–413 (2001).
Goehring, N. W., Gonzalez, M. D. & Beckwith, J. Premature targeting of cell division proteins to midcell reveals hierarchies of protein interactions involved in divisome assembly. Mol. Microbiol. 61, 33–45 (2006).
Lowe, J. & Amos, L. A. Crystal structure of the bacterial cell-division protein FtsZ. Nature 391, 203–206 (1998).
Nogales, E., Wolf, S. G. & Downing, K. H. Structure of the α β tubulin dimer by electron crystallography. Nature 391, 199–203 (1998). The above two papers provided the long sought after three-dimensional structures of tubulin and FtsZ, and left little doubt that these two proteins are evolutionarily related.
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. USA 89, 7290–7294 (1992).
van den Ent, F. & Lowe, J. Crystal structure of the cell division protein FtsA from Thermotoga maritima. EMBO J. 19, 5300–5307 (2000).
Hale, C. A. & de Boer, P. A. Direct binding of FtsZ to ZipA, an essential component of the septal ring structure that mediates cell division in E. coli. Cell 88, 175–185 (1997). This paper presents a clever approach to the identification of the first FtsZ-associating protein in bacteria.
Mosyak, L. 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).
Jennings, L. D. et al. Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA–FtsZ interaction. Bioorg. Med. Chem. 12, 5115–5131 (2004).
Jennings, L. D. et al. Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction. Bioorg. Med. Chem. Lett. 14, 1427–1431 (2004).
Sutherland, A. G. et al. Structure-based design of carboxybiphenylindole inhibitors of the ZipA–FtsZ interaction. Org. Biomol. Chem. 1, 4138–4140 (2003).
Tsao, D. H. et al. Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. Bioorg. Med. Chem. 14, 7953–7961 (2006).
Arkin, M. R. & Wells, J. A. Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nature Rev. Drug Discov. 3, 301–317 (2004). This is an excellent review on the emerging and challenging approaches to drug discovery.
Haney, S. A. et al. Genetic analysis of the Escherichia coli FtsZ–ZipA interaction in the yeast two-hybrid system. Characterization of FtsZ residues essential for the interactions with ZipA and with FtsA. J. Biol. Chem. 276, 11980–11987 (2001).
Hopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).
RayChaudhuri, D. & Park, J. T. Escherichia coli cell-division gene ftsZ encodes a novel GTP-binding protein. Nature 359, 251–254 (1992).
de Boer, P., Crossley, R. & Rothfield, L. The essential bacterial cell-division protein FtsZ is a GTPase. Nature 359, 254–256 (1992).
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). The above three papers report the GTPase activity of FtsZ, several years after identification of the ftsZ gene.
Sanchez, M., Valencia, A., Ferrandiz, M. J., Sander, C. & Vicente, M. Correlation between the structure and biochemical activities of FtsA, an essential cell division protein of the actin family. EMBO J. 13, 4919–4925 (1994).
Lara, B. et al. Cell division in cocci: localization and properties of the Streptococcus pneumoniae FtsA protein. Mol. Microbiol. 55, 699–711 (2005).
Yim, L. et al. Role of the carboxy terminus of Escherichia coli FtsA in self-interaction and cell division. J. Bacteriol. 182, 6366–6373 (2000).
Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534 (1996).
Boehm, H. J. et al. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J. Med. Chem. 43, 2664–2674 (2000).
Sidhu, S. S., Fairbrother, W. J. & Deshayes, K. Exploring protein–protein interactions with phage display. ChemBioChem 4, 14–25 (2003).
Toogood, P. L. Inhibition of protein–protein association by small molecules: approaches and progress. J. Med. Chem. 45, 1543–1558 (2002).
DeLano, W. L., Ultsch, M. H., de Vos, A. M. & Wells, J. A. Convergent solutions to binding at a protein–protein interface. Science 287, 1279–1283 (2000).
McMillan, K. et al. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl Acad. Sci. USA 97, 1506–1511 (2000).
Niederhauser, O. et al. NGF ligand alters NGF signaling via p75(NTR) and trkA. J. Neurosci. Res. 61, 263–272 (2000).
Cheng, Y. et al. Rational drug design via intrinsically disordered protein. Trends Biotechnol. 24, 435–442 (2006).
Oldfield, C. J. et al. Coupled folding and binding with α-helix-forming molecular recognition elements. Biochemistry 44, 12454–12470 (2005).
Wang, J. et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441, 358–361 (2006). This describes the extraordinary discovery of a natural broad-spectrum antibiotic with a novel mode of action.
Bi, E., Dai, K., Subbarao, S., Beall, B. & Lutkenhaus, J. FtsZ and cell division. Res. Microbiol. 142, 249–252 (1991).
Romberg, L. & Levin, P. A. Assembly dynamics of the bacterial cell division protein FTSZ: poised at the edge of stability. Annu. Rev. Microbiol. 57, 125–154 (2003).
White, E. L., Suling, W. J., Ross, L. J., Seitz, L. E. & Reynolds, R. C. 2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ. J. Antimicrob. Chemother. 50, 111–114 (2002).
Reynolds, R. C., Srivastava, S., Ross, L. J., Suling, W. J. & White, E. L. A new 2-carbamoyl pteridine that inhibits mycobacterial FtsZ. Bioorg. Med. Chem. Lett. 14, 3161–3164 (2004).
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. 278, 44424–44428 (2003).
Margalit, D. N. 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).
Lappchen, T., Hartog, A. F., Pinas, V. A., Koomen, G. J. & den Blaauwen, T. GTP analogue inhibits polymerization and GTPase activity of the bacterial protein FtsZ without affecting its eukaryotic homologue tubulin. Biochemistry 44, 7879–7884 (2005).
Stokes, N. R. et al. Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. J. Biol. Chem. 280, 39709–39715 (2005). An example of a screen for inhibitors of bacterial cell division. A clever approach that successfully provided a strong lead that meets several antibacterial criteria.
Paradis-Bleau, C., Sanschagrin, F. & Levesque, R. C. Identification of Pseudomonas aeruginosa FtsZ peptide inhibitors as a tool for development of novel antimicrobials. J. Antimicrob. Chemother. 54, 278–280 (2004).
Beuria, T. K., Santra, M. K. & Panda, D. Sanguinarine blocks cytokinesis in bacteria by inhibiting FtsZ assembly and bundling. Biochemistry 44, 16584–16593 (2005).
Paradis-Bleau, C., Beaumont, M., Sanschagrin, F., Voyer, N. & Levesque, R. C. Parallel solid synthesis of inhibitors of the essential cell division FtsZ enzyme as a new potential class of antibacterials. Bioorg. Med. Chem. 15, 1330–1340 (2007).
Vollmer, W. The prokaryotic cytoskeleton: a putative target for inhibitors and antibiotics? Appl. Microbiol. Biotechnol. 73, 37–47 (2006).
Huang, Q., Tonge, P. J., Slayden, R. A., Kirikae, T. & Ojima, I. FtsZ: a novel target for tuberculosis drug discovery. Curr. Top. Med. Chem. 7, 527–543 (2007).
Dajkovic, A. & Lutkenhaus, J. Z ring as executor of bacterial cell division. J. Mol. Microbiol. Biotechnol. 11, 140–151 (2006).
Margolin, W. FtsZ and the division of prokaryotic cells and organelles. Nature Rev. Mol. Cell Biol. 6, 862–871 (2005).
Michie, K. A. & Lowe, J. Dynamic filaments of the bacterial cytoskeleton. Annu. Rev. Biochem. 75, 467–492 (2006).
Erickson, H. P., Taylor, D. W., Taylor, K. A. & Bramhill, D. Bacterial cell division protein FtsZ assembles into protofilament sheets and minirings, structural homologs of tubulin polymers. Proc. Natl Acad. Sci. USA 93, 519–523 (1996).
Yu, X. C. & Margolin, W. Ca2+-mediated GTP-dependent dynamic assembly of bacterial cell division protein FtsZ into asters and polymer networks in vitro. EMBO J. 16, 5455–5463 (1997).
Mukherjee, A. & Lutkenhaus, J. Dynamic assembly of FtsZ regulated by GTP hydrolysis. EMBO J. 17, 462–469 (1998).
Lowe, J. & Amos, L. A. Tubulin-like protofilaments in Ca2+-induced FtsZ sheets. EMBO J. 18, 2364–2371 (1999).
White, E. L. et al. Slow polymerization of Mycobacterium tuberculosis FtsZ. J. Bacteriol. 182, 4028–4034 (2000).
Romberg, L., Simon, M. & Erickson, H. P. Polymerization of Ftsz, a bacterial homolog of tubulin. Is assembly cooperative? J. Biol. Chem. 276, 11743–11753 (2001).
Oliva, M. A. et al. Assembly of archaeal cell division protein FtsZ and a GTPase-inactive mutant into double-stranded filaments. J. Biol. Chem. 278, 33562–33570 (2003).
Huang, Q. et al. Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. J. Med. Chem. 49, 463–466 (2006).
Weisleder, D. & Lillehoj, E. B. Structure of viriditoxin, a toxic metabolite of Aspergillus viridinutans. Tetrahedron Lett. 48, 4705–4706 (1971).
Urgaonkar, S. et al. Synthesis of antimicrobial natural products targeting FtsZ: (±)-dichamanetin and (±)-2' “-hydroxy-5” '-benzylisouvarinol-B. Org. Lett. 7, 5609–5612 (2005).
Hiraga, S. et al. Chromosome partitioning in Escherichia coli: novel mutants producing anucleate cells. J. Bacteriol. 171, 1496–1505 (1989).
Ito, H. et al. A 4-aminofurazan derivative-A189-inhibits assembly of bacterial cell division protein FtsZ in vitro and in vivo. Microbiol. Immunol. 50, 759–764 (2006).
Jordan, A., Hadfield, J. A., Lawrence, N. J. & McGown, A. T. Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med. Res. Rev. 18, 259–296 (1998).
Verrills, N. M. & Kavallaris, M. Improving the targeting of tubulin-binding agents: lessons from drug resistance studies. Curr. Pharm. Des. 11, 1719–1733 (2005).
Lu, C., Stricker, J. & Erickson, H. P. FtsZ from Escherichia coli, Azotobacter vinelandii, and Thermotoga maritima — quantitation, GTP hydrolysis, and assembly. Cell. Motil. Cytoskeleton 40, 71–86 (1998).
Stricker, J., Maddox, P., Salmon, E. D. & Erickson, H. P. Rapid assembly dynamics of the Escherichia coli FtsZ-ring demonstrated by fluorescence recovery after photobleaching. Proc. Natl Acad. Sci. USA 99, 3171–3175 (2002).
Levin, P. A., Kurtser, I. G. & Grossman, A. D. Identification and characterization of a negative regulator of FtsZ ring formation in Bacillus subtilis. Proc. Natl Acad. Sci. USA 96, 9642–9647 (1999).
Gueiros-Filho, F. J. & Losick, R. A widely conserved bacterial cell division protein that promotes assembly of the tubulin-like protein FtsZ. Genes Dev. 16, 2544–2556 (2002).
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. 60, 1364–1380 (2006).
Lutkenhaus, J. F. & Donachie, W. D. Identification of the FTSA gene product. J. Bacteriol. 137, 1088–1094 (1979).
Beall, B. & Lutkenhaus, J. Impaired cell division and sporulation of a Bacillus subtilis strain with the ftsA gene deleted. J. Bacteriol. 174, 2398–2403 (1992).
Paradis-Bleau, C., Sanschagrin, F. & Levesque, R. C. Peptide inhibitors of the essential cell division protein FtsA. Protein Eng. Des. Sel. 18, 85–91 (2005).
Pichoff, S. & Lutkenhaus, J. Identification of a region of FtsA required for interaction with FtsZ. Mol. Microbiol. 64, 1129–1138 (2007).
Pichoff, S. & Lutkenhaus, J. Tethering the Z ring to the membrane through a conserved membrane targeting sequence in FtsA. Mol. Microbiol. 55, 1722–1734 (2005). A significant discovery regarding the role of FtsA in cell division that will significantly aid in the determination of the function of this elusive protein.
Dai, K. & Lutkenhaus, J. The proper ratio of FtsZ to FtsA is required for cell division to occur in Escherichia coli. J. Bacteriol. 174, 6145–6151 (1992).
Yan, K., Pearce, K. H. & Payne, D. J. A conserved residue at the extreme C-terminus of FtsZ is critical for the FtsA–FtsZ interaction in Staphylococcus aureus. Biochem. Biophys. Res. Commun. 270, 387–392 (2000).
Tamura, M. et al. RNase E maintenance of proper FtsZ/FtsA ratio required for nonfilamentous growth of Escherichia coli cells but not for colony-forming ability. J. Bacteriol. 188, 5145–5152 (2006).
Wang, X., Huang, J., Mukherjee, A., Cao, C. & Lutkenhaus, J. Analysis of the interaction of FtsZ with itself, GTP, and FtsA. J. Bacteriol. 179, 5551–5559 (1997).
Din, N., Quardokus, E. M., Sackett, M. J. & Brun, Y. V. Dominant C-terminal deletions of FtsZ that affect its ability to localize in Caulobacter and its interaction with FtsA. Mol. Microbiol 27, 1051–1063 (1998).
Ma, X. & Margolin, W. Genetic and functional analyses of the conserved C-terminal core domain of Escherichia coli FtsZ. J. Bacteriol. 181, 7531–7544 (1999).
Hale, C. A. & de Boer, P. A. J. ZipA is required for recruitment of FtsK, FtsQ, FtsL, and FtsN to the septal ring in Escherichia coli. J. Bacteriol. 184, 2552–2556 (2002).
Corbin, B. D., Geissler, B., Sadasivam, M. & Margolin, W. Z-Ring-independent interaction between a subdomain of FtsA and late septation proteins as revealed by a polar recruitment assay. J. Bacteriol. 186, 7736–7744 (2004).
Rico, A. I., Garcia-Ovalle, M., Mingorance, J. & Vicente, M. Role of two essential domains of Escherichia coli FtsA in localization and progression of the division ring. Mol. Microbiol. 53, 1359–1371 (2004).
Goehring, N. W., Petrovska, I., Boyd, D. & Beckwith, J. Mutants, suppressors, and wrinkled colonies: mutant alleles of the cell division gene ftsQ point to functional domains in FtsQ and a role for domain 1C of FtsA in divisome assembly. J. Bacteriol. 189, 633–645 (2007).
Goehring, N. W., Gueiros-Filho, F. & Beckwith, J. Premature targeting of a cell division protein to midcell allows dissection of divisome assembly in Escherichia coli. Genes Dev. 19, 127–137 (2005).
Hale, C. A. & de Boer, P. A. Recruitment of ZipA to the septal ring of Escherichia coli is dependent on FtsZ and independent of FtsA. J. Bacteriol. 181, 167–176 (1999).
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).
Hale, C., Rhee, A. & de Boer, P. ZipA-induced bundling of FtsZ polymers mediated by an interaction between C-terminal domains. J. Bacteriol. 182, 5153–5166 (2000).
RayChaudhuri, D. ZipA is a MAP-Tau homolog and is essential for structural integrity of the cytokinetic FtsZ ring during bacterial cell division. EMBO J. 18, 2372–2383 (1999).
Ohashi, T., Hale, C. A., de Boer, P. A. & Erickson, H. P. Structural evidence that the P/Q domain of ZipA is an unstructured, flexible tether between the membrane and the C-terminal FtsZ-binding domain. J. Bacteriol. 184, 4313–4315 (2002).
Liu, Z., Mukherjee, A. & Lutkenhaus, J. Recruitment of ZipA to the division site by interaction with FtsZ. Mol. Microbiol. 31, 1853–1861 (1999).
Moy, F. J., Glasfeld, E., Mosyak, L. & Powers, R. Solution structure of ZipA, a crucial component of Escherichia coli cell division. Biochemistry 39, 9146–9156 (2000).
Rush, T. S. 3rd, Grant, J. A., Mosyak, L. & Nicholls, A. A shape-based 3-D scaffold hopping method and its application to a bacterial protein–protein interaction. J. Med. Chem. 48, 1489–1495 (2005).
Moreira, I. S., Fernandes, P. A. & Ramos, M. J. Detailed microscopic study of the full zipA:FtsZ interface. Proteins 63, 811–821 (2006).
Low, H. H., Moncrieffe, M. C. & Lowe, J. The crystal structure of ZapA and its modulation of FtsZ polymerisation. J. Mol. Biol. 341, 839–852 (2004).
Schmidt, K. L. et al. A predicted ABC transporter, FtsEX, is needed for cell division in Escherichia coli. J. Bacteriol. 186, 785–793 (2004).
Corbin, B. D., Wang, Y., Beuria, T. K. & Margolin, W. Interaction between cell division proteins FtsE and FtsZ. J. Bacteriol. 189, 3026–3035 (2007).
Reddy, M. Role of FtsEX in cell division of Escherichia coli: viability of ftsEX mutants is dependent on functional SufI or high osmotic strength. J. Bacteriol. 189, 98–108 (2007).
Miyagishima, S.-Y. et al. Two types of FtsZ proteins in mitochondria and red-linage chloroplasts: the duplication of FtsZ is implicated in endosymbiosis. J. Mol. Evol. 58, 291–303 (2004).
Hamoen, L. W., Meile, J. C., 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).
Miyagishima, S. -Y., Wolk, C. P. & Osteryoung, K. W. Identification of cyanobacterial cell division genes by comparative and mutational analyses. Mol. Microbiol. 56, 126–143 (2005).
Aarsman, M. E. G. et al. Maturation of the Escherichia coli divisome occurs in two steps. Mol. Microbiol. 55, 1631–1645 (2005).
Den Blaauwen, T., Buddelmeijer, N., Aarsman, M. E. G., Hameete, C. M. & Nanninga, N. Timing of FtsZ assembly in Escherichia coli. J. Bacteriol. 181, 5167–5175 (1999).
Schmid, M. B. Crystallizing new approaches for antimicrobial drug discovery. Biochem. Pharmacol. 71, 1048–1056 (2006). An excellent review demonstrating challenging state-of-the-art approaches to antibacterials.
Barre, F. X. et al. The replication-recombination-chromosome segregation connection. Proc. Natl Acad. Sci. USA 98, 8189–8195 (2001).
Wu, L. J. & Errington, J. Bacillus subtilis spoIIIE protein required for DNA segregation during asymmetric cell division. Science 264, 572–575 (1994).
Goffin, C. & Ghuysen, J. M. Multimodular penicillin-binding proteins: an enigmatic family of orthologs and paralogs. Microbiol. Mol. Biol. Rev. 62, 1079–1093 (1998).
Holtje, J. V. Growth of the stress-bearing and shape-maintaining murein sacculus of Escherichia coli. Microbiol. Mol. Biol. Rev. 62, 181–203 (1998).
Scheffers, D. J. & Pinho, M. G. Bacterial cell wall synthesis: new insights from localization studies. Microbiol. Mol. Biol. Rev. 69, 585–607 (2005). A key review on the current understanding of the PBPs and their role in growth and cell division.
Kell, C. M. et al. Deletion analysis of the essentiality of penicillin-binding proteins 1A, 2B and 2X of Streptococcus pneumoniae. FEMS Microbiol. Lett. 106, 171–175 (1993).
Daniel, R. A., Williams, A. M. & Errington, J. A complex four-gene operon containing essential cell division gene pbpB in Bacillus subtilis. J. Bacteriol. 178, 2343–2350 (1996).
Pinho, M. G., de Lencastre, H. & Tomasz, A. Cloning, characterization, and inactivation of the gene pbpC, encoding penicillin-binding protein 3 of Staphylococcus aureus. J. Bacteriol. 182, 1074–1079 (2000).
Pereira, S. F., Henriques, A. O., Pinho, M. G., de Lencastre, H. & Tomasz, A. Role of PBP1 in cell division of Staphylococcus aureus. J. Bacteriol. 189, 3525–3531 (2007).
Morlot, C., Zapun, A., Dideberg, O. & Vernet, T. Growth and division of Streptococcus pneumoniae: localization of the high molecular weight penicillin-binding proteins during the cell cycle. Mol. Microbiol. 50, 845–855 (2003).
Boyle, D. S., Khattar, M. M., Addinall, S. G., Lutkenhaus, J. & Donachie, W. D. ftsW is an essential cell-division gene in Escherichia coli. Mol. Microbiol 24, 1263–1273 (1997).
Henriques, A. O., Glaser, P., Piggot, P. J. & Moran, C. P. Jr. Control of cell shape and elongation by the rodA gene in Bacillus subtilis. Mol. Microbiol. 28, 235–247 (1998).
Mercer, K. L. & Weiss, D. S. The Escherichia coli cell division protein FtsW is required to recruit its cognate transpeptidase, FtsI (PBP3), to the division site. J. Bacteriol. 184, 904–912 (2002).
Datta, P. et al. Interaction between FtsW and penicillin-binding protein 3 (PBP3) directs PBP3 to mid-cell, controls cell septation and mediates the formation of a trimeric complex involving FtsZ, FtsW and PBP3 in mycobacteria. Mol. Microbiol. 62, 1655–1673 (2006).
Datta, P., Dasgupta, A., Bhakta, S. & Basu, J. Interaction between FtsZ and FtsW of Mycobacterium tuberculosis. J. Biol. Chem. 277, 24983–24987 (2002).
Storts, D. R., Aparicio, O. M., Schoemaker, J. M. & Markovitz, A. Overproduction and identification of the ftsQ gene product, an essential cell division protein in Escherichia coli K-12. J. Bacteriol. 171, 4290–4297 (1989).
Buddelmeijer, N., Judson, N., Boyd, D., Mekalanos, J. J. & Beckwith, J. YgbQ, a cell division protein in Escherichia coli and Vibrio cholerae, localizes in codependent fashion with FtsL to the division site. Proc. Natl Acad. Sci. USA 99, 6316–6321 (2002).
Guzman, L. M., Barondess, J. J. & Beckwith, J. FtsL, an essential cytoplasmic membrane protein involved in cell division in Escherichia coli. J. Bacteriol. 174, 7716–7728 (1992).
Di Lallo, G., Fagioli, M., Barionovi, D., Ghelardini, P. & Paolozzi, L. Use of a two-hybrid assay to study the assembly of a complex multicomponent protein machinery: bacterial septosome differentiation. Microbiology 149, 3353–3359 (2003).
Karimova, G., Dautin, N. & Ladant, D. Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis. J. Bacteriol. 187, 2233–2243 (2005).
Noirclerc-Savoye, M. et al. In vitro reconstitution of a trimeric complex of DivIB, DivIC and FtsL, and their transient co-localization at the division site in Streptococcus pneumoniae. Mol. Microbiol. 55, 413–424 (2005).
Daniel, R. A., Noirot-Gros, M. F., Noirot, P. & Errington, J. Multiple interactions between the transmembrane division proteins of Bacillus subtilis and the role of FtsL instability in divisome assembly. J. Bacteriol. 188, 7396–7404 (2006).
Levin, P. A. & Losick, R. Characterization of a cell division gene from Bacillus subtilis that is required for vegetative and sporulation septum formation. J. Bacteriol. 176, 1451–1459 (1994).
Daniel, R. A., Harry, E. J., Katis, V. L., Wake, R. G. & Errington, J. Characterization of the essential cell division gene ftsL(yIID) of Bacillus subtilis and its role in the assembly of the division apparatus. Mol. Microbiol. 29, 593–604 (1998).
Beall, B. & Lutkenhaus, J. Nucleotide sequence and insertional inactivation of a Bacillus subtilis gene that affects cell division, sporulation, and temperature sensitivity. J. Bacteriol. 171, 6821–6834 (1989).
Katis, V. L., Wake, R. G. & Harry, E. J. Septal localization of the membrane-bound division proteins of Bacillus subtilis DivIB and DivIC is codependent only at high temperatures and requires FtsZ. J. Bacteriol. 182, 3607–3611 (2000).
Robson, S. A., Michie, K. A., Mackay, J. P., Harry, E. & King, G. F. The Bacillus subtilis cell division proteins FtsL and DivIC are intrinsically unstable and do not interact with one another in the absence of other septasomal components. Mol. Microbiol. 44, 663–674 (2002).
D'Ulisse, V., Fagioli, M., Ghelardini, P. & Paolozzi, L. Three functional subdomains of the Escherichia coli FtsQ protein are involved in its interaction with the other division proteins. Microbiology 153, 124–138 (2007).
Sanchez-Pulido, L., Devos, D., Genevrois, S., Vicente, M. & Valencia, A. POTRA: a conserved domain in the FtsQ family and a class of β-barrel outer membrane proteins. Trends Biochem. Sci. 28, 523–526 (2003).
Robson, S. A. & King, G. F. Domain architecture and structure of the bacterial cell division protein DivIB. Proc. Natl Acad. Sci. USA 103, 6700–6705 (2006).
Thompson, L. S., Beech, P. L., Real, G., Henriques, A. O. & Harry, E. J. Requirement for the cell division protein DivIB in polar cell division and engulfment during sporulation in Bacillus subtilis. J. Bacteriol. 188, 7677–7685 (2006).
Sievers, J. & Errington, J. Analysis of the essential cell division gene ftsL of Bacillus subtilis by mutagenesis and heterologous complementation. J. Bacteriol. 182, 5572–5579 (2000).
Daniel, R. A. & Errington, J. Intrinsic instability of the essential cell division protein FtsL of Bacillus subtilis and a role for DivIB protein in FtsL turnover. Mol. Microbiol. 36, 278–289 (2000).
Romero-Tabarez, M. et al. 7-O-malonyl macrolactin A, a new macrolactin antibiotic from Bacillus subtilis active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and a small-colony variant of Burkholderia cepacia. Antimicrob. Agents Chemother. 50, 1701–1709 (2006).
Si, W. et al. Bioassay-guided purification and identification of antimicrobial components in Chinese green tea extract. J. Chromatogr. A 1125, 204–210 (2006).
Watt, P. M. Screening for peptide drugs from the natural repertoire of biodiverse protein folds. Nature Biotech. 24, 177–183 (2006).
Keller, T. H., Pichota, A. & Yin, Z. A practical view of 'druggability'. Curr. Opin. Chem. Biol. 10, 357–361 (2006).
Dai, K. & Lutkenhaus, J. ftsZ is an essential cell division gene in Escherichia coli. J. Bacteriol. 173, 3500–3506 (1991).
Wang, L., Khattar, M. K., Donachie, W. D. & Lutkenhaus, J. FtsI and FtsW are localized to the septum in Escherichia coli. J. Bacteriol. 180, 2810–2816 (1998).
Espeli, O., Lee, C. & Marians, K. J. A physical and functional interaction between Escherichia coli FtsK and topoisomerase IV. J. Biol. Chem. 278, 44639–44644 (2003).
Massey, T. H., Mercogliano, C. P., Yates, J., Sherratt, D. J. & Lowe, J. Double-stranded DNA translocation: structure and mechanism of hexameric FtsK. Mol. Cell 23, 457–469 (2006).
Spratt, B. G. Properties of the penicillin-binding proteins of Escherichia coli K12. Eur. J. Biochem. 72, 341–352 (1977).
Dessen, A., Mouz, N., Gordon, E., Hopkins, J. & Dideberg, O. Crystal structure of PBP2x from a highly penicillin-resistant Streptococcus pneumoniae clinical isolate: a mosaic framework containing 83 mutations. J. Biol. Chem. 276, 45106–45112 (2001).
Yang, J. C., Van Den Ent, F., Neuhaus, D., Brevier, J. & Lowe, J. Solution structure and domain architecture of the divisome protein FtsN. Mol. Microbiol. 52, 651–660 (2004).
Bernhardt, T. G. & de Boer, P. A. The Escherichia coli amidase AmiC is a periplasmic septal ring component exported via the twin-arginine transport pathway. Mol. Microbiol. 48, 1171–1182 (2003).
Heidrich, C. et al. Involvement of N-acetylmuramyl-L-alanine amidases in cell separation and antibiotic-induced autolysis of Escherichia coli. Mol. Microbiol. 41, 167–178 (2001).
Kobayashi, K. et al. Essential Bacillus subtilis genes. Proc. Natl Acad. Sci. USA 100, 4678–4683 (2003).
Bernhardt, T. G. & de Boer, P. A. Screening for synthetic lethal mutants in Escherichia coli and identification of EnvC (YibP) as a periplasmic septal ring factor with murein hydrolase activity. Mol. Microbiol. 52, 1255–1269 (2004).
Song, J. H. et al. Identification of essential genes in Streptococcus pneumoniae by allelic replacement mutagenesis. Mol. Cells 19, 365–374 (2005).
Ecker, D. J. et al. The Microbial Rosetta Stone Database: a compilation of global and emerging infectious microorganisms and bioterrorist threat agents. BMC Microbiol. 5, 19 (2005).
Acknowledgements
We thank L. Monahan (Institute for the Biotechnology of Infectious Diseases, University of Technology, Sydney) for contributions to table 1 and for figure 3.
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R.L.L. and E.J.H. are employees of the University of Technology, Sydney, Australia, and are working in collaboration with Proteome Systems Ltd in the discovery and commercialization of therapeutic targets for the treatment of antibacterial infections.
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Glossary
- Peptidoglycan
-
Also known as murein, is a polymer consisting of sugars and amino acids that is located outside the cytoplasmic membrane of eubacteria. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine and N-acetylmuramic acid. Attached to the N-acetylmuramic acid is a peptide chain of three to five amino acids. Strands are crosslinked by their peptide chains, providing a rigid three-dimensional matrix. The peptidoglycan layer is substantially thicker in Gram-positive bacteria (20–80 nm) than in Gram-negative bacteria (7–8 nm).
- Bactericidal
-
Kills bacteria.
- Divisome
-
Proteins that make up the septal ring at the division site in bacteria.
- Fragment-discovery approach
-
A method devised recently for probing a large chemical space while synthesizing a minimum number of compounds. Fragments are usually organic compounds of small molecular mass that bind a protein target, which are then optimized for improved function, allowing enrichment for binding to the target.
- Phage display
-
A high-throughput assay for protein–protein or protein–small molecule interactions by cloning genes of interest for display on the surface of a bacteriophage.
- Hot spots
-
Compact, centralized regions of residues at a protein–protein interface that are crucial for the affinity of the interaction. They tend to be found on both sides of the interface and are highly complementary to each other in crystal structures.
- Allosteric protein
-
A protein containing two or more topologically distinct binding sites that interact functionally with each other.
- Sporulation
-
Differentiation of a vegetative bacterial cell to form a spore, a dormant cell type, in response to nutrient depletion. The process involves a regulated programme of differential gene expression and the formation of an asymmetric division septum.
- Peptidomimetic
-
A compound that has been designed to mimic the functionality of a short peptide sequence that interacts with a receptor site in a protein–protein interaction, offering the advantages of increased bioavailability, biostability, bioefficiency and bioselectivity.
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Lock, R., Harry, E. Cell-division inhibitors: new insights for future antibiotics. Nat Rev Drug Discov 7, 324–338 (2008). https://doi.org/10.1038/nrd2510
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DOI: https://doi.org/10.1038/nrd2510
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