FtsZ – Bacterial homologue to tubulin and target for new antibiotics

Structure

Fig 1: Structure of FtsZ protein determined by X-ray crystallography (4) and oligomeric structure arranged from the monomer (5).

The unprecedented increase in antibiotic-resistant pathogens and lack of new antibiotic development highlights the need for new anti-microbial drugs active against novel targets such as bacterial cell division proteins.  Recently, FtsZ (Filamenting temperature sensitive mutant Z) has become the focus of antibiotic research as a novel target for new anti-microbials (1, 2).

The FtsZ protein is essential for bacterial cell division.  Mutants lacking this protein do not divide, but continue to elongate into filaments.  FtsZ is a GTPase (3) that polymerizes in a nucleotide-dependent manner head-to-tail to form single-stranded filaments (Fig 1) that assemble into a contractile ring (6).  The ring is called the Z-ring and forms on the inside of the cytoplasmic membrane where it marks the future site of the septum of a dividing bacterial cell. Although FtsZ polymerization rapidly reaches steady state, the Z-ring is dynamically maintained through the course of cell division by continuous and rapid turnover of FtsZ polymers (7), likely fueled by FtsZ’s GTP hydrolysis (3).  FtsZ is the first protein to localize at the division site and recruits other proteins involved in bacterial cell division.  Besides serving as a scaffold for the other cell division proteins, FtsZ itself may exert cytokinetic forces that lead to cell division (8-10).

FtsZ is a prokaryotic homologue to the eukaryotic tubulin

FtsZ has structural similarity to the eukaryotic tubulin (2), and hence is considered a prokaryotic homolog to this protein (11).  Both tubulin and FtsZ contain a GTP-binding domain, have GTPase activity, assemble into protofilaments, two-dimensional sheets, and protofilament rings, and share substantial structural identities.  Despite these parallels, FtsZ and tubulin only share 10-18% sequence similarity and the basic subunit of FtsZ is a monomer, whereas the tubulin subunit is an alpha and beta heterodimer.

FtsZ inhibition

Fig 2: Polymerization of FtsZ protein from E.coli (panel A, Cat. FTZ05) and S. aureus (panel B, Cat. FTZ02) in the presence of 15 µM FtsZ inhibitor PC190723 (red line) or buffer only (green line). GTPase activity was measured with a MESG-based assay (Cat. BK052) using 0.3 mg/ml E.coli FtsZ or 1.0 mg/ml S. aureus FtsZ

FtsZ as a pharmacological target

The amino-acid sequence identity between different FtsZ species is 35 to 99%, and most commonly 40 to 70%.  This low to medium level of homology affects drug discovery in two ways: 1. Using one FtsZ protein target will likely generate a highly specific drug to that species, and conversely, 2. It is unlikely that a broad spectrum anti-bacterial FtsZ ligand will be identified.  Indeed, Haydon et al (12) reported that PC190723, a Staphylococcus aureus FtsZ inhibitor also inhibited FtsZ from Bacillus subtilis, which is 70% homologous to S.aureus FtsZ, but did not inhibit FtsZ isolated from Escherichia coli which has 51% and 47% homology, respectively (Fig 2).

FtsZ related products available

To enable researchers to run experiments with FtsZ protein and to screen for inhibitors of polymerisation which might serve as new antibiotic drugs, our partner Cytoskeleton Inc. offers FtsZ proteins from different bacterial species:

Furthermore, tebu-bio offers two Anti FtsZ Antibodies.

If you are interested in these exciting proteins, leave your comments below.

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References:

  • (1) Sass P, Josten M, Famulla K, Schiffer G, Sahl H-G, Hamoen L. and Brötz-Oesterhelt H. (2011). Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc. Natl. Acad. Sci. USA. 108, 17474-17479.
  • (2) Mathew B, Srivastava S, Ross LJ, Suling WJ, White EL, Woolhiser LK, Lenaerts AJ, Reynolds RC. (2011). Novel pyridopyrazine and pyrimidothiazine derivatives as FtsZ inhibitors. Bioorg. Med. Chem. 19, 7120-7128.
  • (3) de Boer P, Crossley R, and Rothfield A. (1992). The essential bacterial cell-division protein FtsZ is a GTPase. Nature. 359, 254-256.
  • (4) Lowe J and Amos LA. (1998). Crystal structure of the bacterial cell-division protein FtsZ. Nature. 391, 203-206.
  • (5) Aylett CHS, Wang Q, Michie, KA, Amos LA, and Lowe J. (2010). Filament structure of bacterial tubulin homologue TubZ. Proc. Natl. Acad. Sci. USA. 107, 19766-19771.
  • (6) Bi E and Lutkenhaus J. (1991). FtsZ ring structure associated with division in Escherichia coli. Nature. 354, 161-164
  • (7) Popp D and Robertson RD. (2010). Suprastructures and dynamic properties of Mycobacterium tuberculosis FtsZ. J. Biol. Chem. 15, 11281-11289.
  • (8) Romberg L. and Levin PA. (2003). Assembly dynamics of the bacterial cell division protein FtsZ: Poised at the edge of stability. Annu. Rev. Microbiol. 57, 125-154.
  • (9) Erickson HP, Anderson DE, and Osawa M. (2010). FtsZ in bacterial cytokinesis: cytoskeleton and force generator all in one. Microbiol. Mol. Biol. Rev. 74, 504-528.
  • (10) Mingorance J, Rivas G, Vélez M, Gómez-Puertas P, Vicente M. (2010). Strong FtsZ is with the force: mechanisms to constrict bacteria. Trends Microbiol. 18, 348–56.
  • (11) Erickson HP. (1995). FtsZ, a prokaryotic homolog of tubulin? Cell. 80, 367-370
  • (12) Haydon DJ, Bennett JM, Brown D, et al (20 authors) (2010). Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties. J. Med. Chem. 53, 3927-3936.

Thanks to our colleagues from Cytoskeleton Inc who provided the material for this blog.

 

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Written by Ali El Baya, PhD
Ali el Bayâ is the Sales Manager at tebu-bio for the North of Europe.