Novel compound with potential of an antibacterial drug targets FtsZ protein

2009 ◽  
Vol 423 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Dipak Dasgupta
Keyword(s):  
Cell Division ◽  
Self Assembly ◽  
Drug Targets ◽  
Antibacterial Drug ◽  
Bacterial Cell Division ◽  
Normal Functioning ◽  
Ftsz Protein ◽  
Biochemical Journal ◽  
Z Ring ◽  
Dissociation Step

A dynamic bacterial cytoskeleton consisting of FtsZ and other proteins is a potential target for the development of antibacterial drugs. GTPase activity of FtsZ protein leads to self-assembly of the protein. The resultant circumferential dynamic Z-ring at the centre of the cell recruits other proteins during progression and completion of bacterial cell division. There are natural compounds inhibiting one or more of these steps. Such inhibition ultimately culminates in the arrest of cell division. In this issue of the Biochemical Journal, a paper by Beuria et al. highlights the importance of the dynamics of the Z-ring for cell division. The ligand-induced enhanced degree of stabilization of FtsZ protofilaments, leading to the absence of the subsequent dissociation step, would hamper the normal functioning of the Z-ring, leading to an inhibition of cell proliferation. A novel antibacterial agent, OTBA (3-{5-[4-oxo-2-thioxo-3-(3-trifluoromethylphenyl)-thiazolidin-5-ylidenemethyl]-furan-2-yl}-benzoic acid) works via this hitherto unreported pathway. It stabilizes the FtsZ polymers, suppressing the dynamics which, in turn, inhibits cell division.

scholarly journals The key bacterial cell division protein FtsZ as a novel antibacterial drug target

2020 ◽  
Author(s):  
Mujeeb Rahman ◽  
Ping Wang ◽  
Na Wang ◽  
Yaodong Chen
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Drug Targets ◽  
Multidrug Resistant ◽  
Antibacterial Drug ◽  
Bacterial Cell Division ◽  
Bacterial Strains ◽  
Antimicrobial Drugs ◽  
Novel Antibiotics

The number of multidrug-resistant bacterial strains is currently increasing; thus, the determination of drug targets for the development of novel antimicrobial drugs is urgently needed. FtsZ, the prokaryotic homolog of the eukaryotic tubulin, is a GTP-dependent prokaryotic cytoskeletal protein that is conserved among most bacterial strains. In vitro studies revealed that FtsZ self-assembles into dynamic protofilaments or bundles, and it forms a dynamic Z-ring at the center of the cell, leading to septation and consequent cell division. The potential role of FtsZ in the blockage of cell division makes FtsZ a highly attractive target for developing novel antibiotics. Researchers have been working on synthetic molecules and natural products as inhibitors of FtsZ. Accumulating data suggest that FtsZ may provide the platform for the development of novel antibiotics. In this review, we summarize recent advances on the properties of FtsZ protein and bacterial cell division, as well as on the development of FtsZ inhibitors.

scholarly journals Lateral interactions between protofilaments of the bacterial tubulin homolog FtsZ are essential for cell division

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Fenghui Guan ◽  
Jiayu Yu ◽  
Jie Yu ◽  
Yang Liu ◽  
Ying Li ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Dynamic Structure ◽  
Living Cells ◽  
Lateral Interactions ◽  
Bacterial Cell Division ◽  
Z Ring ◽  
Crystallographic Structures ◽  
Order Structures

The prokaryotic tubulin homolog FtsZ polymerizes into protofilaments, which further assemble into higher-order structures at future division sites to form the Z-ring, a dynamic structure essential for bacterial cell division. The precise nature of interactions between FtsZ protofilaments that organize the Z-ring and their physiological significance remain enigmatic. In this study, we solved two crystallographic structures of a pair of FtsZ protofilaments, and demonstrated that they assemble in an antiparallel manner through the formation of two different inter-protofilament lateral interfaces. Our in vivo photocrosslinking studies confirmed that such lateral interactions occur in living cells, and disruption of the lateral interactions rendered cells unable to divide. The inherently weak lateral interactions enable FtsZ protofilaments to self-organize into a dynamic Z-ring. These results have fundamental implications for our understanding of bacterial cell division and for developing antibiotics that target this key process.

scholarly journals MinC, MinD, and MinE Drive Counter-oscillation of Early-Cell-Division Proteins Prior to Escherichia coli Septum Formation

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Paola Bisicchia ◽  
Senthil Arumugam ◽  
Petra Schwille ◽  
David Sherratt
Keyword(s):  
Escherichia Coli ◽  
Cell Division ◽  
Lipid Bilayers ◽  
Epifluorescence Microscopy ◽  
Bacterial Cell Division ◽  
Content Type ◽  
Septum Formation ◽  
Early Stages ◽  
Z Ring ◽  
High Concentrations

ABSTRACTBacterial cell division initiates with the formation of a ring-like structure at the cell center composed of the tubulin homolog FtsZ (the Z-ring), which acts as a scaffold for the assembly of the cell division complex, the divisome. Previous studies have suggested that the divisome is initially composed of FtsZ polymers stabilized by membrane anchors FtsA and ZipA, which then recruit the remaining division proteins. The MinCDE proteins prevent the formation of the Z-ring at poles by oscillating from pole to pole, thereby ensuring that the concentration of the Z-ring inhibitor, MinC, is lowest at the cell center. We show that prior to septum formation, the early-division proteins ZipA, ZapA, and ZapB, along with FtsZ, assemble into complexes that counter-oscillate with respect to MinC, and with the same period. We propose that FtsZ molecules distal from high concentrations of MinC form relatively slowly diffusing filaments that are bound by ZapAB and targeted to the inner membrane by ZipA or FtsA. These complexes may facilitate the early stages of divisome assembly at midcell. As MinC oscillates toward these complexes, FtsZ oligomerization and bundling are inhibited, leading to shorter or monomeric FtsZ complexes, which become less visible by epifluorescence microscopy because of their rapid diffusion. Reconstitution of FtsZ-Min waves on lipid bilayers shows that FtsZ bundles partition away from high concentrations of MinC and that ZapA appears to protect FtsZ from MinC by inhibiting FtsZ turnover.IMPORTANCEA big issue in biology for the past 100 years has been that of how a cell finds its middle. InEscherichia coli, over 20 proteins assemble at the cell center at the time of division. We show that the MinCDE proteins, which prevent the formation of septa at the cell pole by inhibiting FtsZ, drive the counter-oscillation of early-cell-division proteins ZapA, ZapB, and ZipA, along with FtsZ. We propose that FtsZ forms filaments at the pole where the MinC concentration is the lowest and acts as a scaffold for binding of ZapA, ZapB, and ZipA: such complexes are disassembled by MinC and reform within the MinC oscillation period before accumulating at the cell center at the time of division. The ability of FtsZ to be targeted to the cell center in the form of oligomers bound by ZipA and ZapAB may facilitate the early stages of divisome assembly.

Z Ring as Executor of Bacterial Cell Division

2006 ◽  
Vol 11 (3-5) ◽  
pp. 140-151 ◽  
Author(s):  
Alex Dajkovic ◽  
Joe Lutkenhaus
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Bacterial Cell Division ◽  
Z Ring

scholarly journals Architecture of the ring formed by the tubulin homologue FtsZ in bacterial cell division

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Piotr Szwedziak ◽  
Qing Wang ◽  
Tanmay A M Bharat ◽  
Matthew Tsim ◽  
Jan Löwe
Keyword(s):  
Cell Division ◽  
Molecular Model ◽  
Three Dimensional ◽  
Bacterial Cell Division ◽  
Electron Cryomicroscopy ◽  
E Coli ◽  
Ftsz Ring ◽  
Z Ring

Membrane constriction is a prerequisite for cell division. The most common membrane constriction system in prokaryotes is based on the tubulin homologue FtsZ, whose filaments in E. coli are anchored to the membrane by FtsA and enable the formation of the Z-ring and divisome. The precise architecture of the FtsZ ring has remained enigmatic. In this study, we report three-dimensional arrangements of FtsZ and FtsA filaments in C. crescentus and E. coli cells and inside constricting liposomes by means of electron cryomicroscopy and cryotomography. In vivo and in vitro, the Z-ring is composed of a small, single-layered band of filaments parallel to the membrane, creating a continuous ring through lateral filament contacts. Visualisation of the in vitro reconstituted constrictions as well as a complete tracing of the helical paths of the filaments with a molecular model favour a mechanism of FtsZ-based membrane constriction that is likely to be accompanied by filament sliding.

scholarly journals Modification of cell wall polysaccharide spatially controls cell division in Streptococcus mutans

2020 ◽  
Author(s):  
Svetlana Zamakhaeva ◽  
Catherine T. Chaton ◽  
Jeffrey S. Rush ◽  
Sowmya Ajay Castro ◽  
Alexander E. Yarawsky ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Division ◽  
Streptococcus Mutans ◽  
Cell Separation ◽  
Ring Structure ◽  
Cell Wall Polysaccharide ◽  
Bacterial Cell Division ◽  
Glycerol Phosphate ◽  
Immature Form ◽  
Z Ring

AbstractBacterial cell division is driven by a tubulin homolog FtsZ, which assembles into the Z-ring structure leading to the recruitment of the cell division machinery. In ovoid-shaped Gram-positive bacteria, such as streptococci, MapZ guides Z-ring positioning at cell equators through an, as yet, unknown mechanism. The cell wall of the important dental pathogen Streptococcus mutans is composed of peptidoglycan decorated with Serotype c Carbohydrates (SCCs). Here, we show that an immature form of SCC, lacking the recently identified glycerol phosphate (GroP) modification, coordinates Z-ring positioning. Pulldown assays using S. mutans cell wall combined with binding affinity analysis identified the major cell separation autolysin, AtlA, as an SCC binding protein. Importantly, AtlA binding to mature SCC is attenuated due to GroP modification. Using fluorescently-labeled AtlA, we mapped SCC distribution on the streptococcal surface to reveal that GroP-deficient immature SCCs are exclusively present at the cell poles and equators. Moreover, the equatorial GroP-deficient SCCs co-localize with MapZ throughout the S. mutans cell cycle. Consequently, in GroP-deficient mutant bacteria, proper AtlA localization is abrogated resulting in dysregulated cellular autolysis. In addition, these mutants display morphological abnormalities associated with MapZ mislocalization leading to Z-ring misplacement. Altogether, our data support a model in which GroP-deficient immature SCCs spatially coordinate the localization of AtlA and MapZ. This mechanism ensures cell separation by AtlA at poles and Z-ring alignment with the cell equator.Graphical abstract

scholarly journals LocZ Is a New Cell Division Protein Involved in Proper Septum Placement in Streptococcus pneumoniae

mBio ◽  
2014 ◽  
Vol 6 (1) ◽  
Author(s):  
Nela Holečková ◽  
Linda Doubravová ◽  
Orietta Massidda ◽  
Virginie Molle ◽  
Karolína Buriánková ◽  
...  
Keyword(s):  
Cell Division ◽  
Streptococcus Pneumoniae ◽  
Protein Kinase ◽  
Bacterial Cell Division ◽  
Content Type ◽  
Daughter Cells ◽  
Division Site ◽  
Z Ring ◽  
Specific Shape ◽  
Cell Division Protein

ABSTRACTHow bacteria control proper septum placement at midcell, to guarantee the generation of identical daughter cells, is still largely unknown. Although different systems involved in the selection of the division site have been described in selected species, these do not appear to be widely conserved. Here, we report that LocZ (Spr0334), a newly identified cell division protein, is involved in proper septum placement inStreptococcus pneumoniae. We show thatlocZis not essential but that its deletion results in cell division defects and shape deformation, causing cells to divide asymmetrically and generate unequally sized, occasionally anucleated, daughter cells. LocZ has a unique localization profile. It arrives early at midcell, before FtsZ and FtsA, and leaves the septum early, apparently moving along with the equatorial rings that mark the future division sites. Consistently, cells lacking LocZ also show misplacement of the Z-ring, suggesting that it could act as a positive regulator to determine septum placement. LocZ was identified as a substrate of the Ser/Thr protein kinase StkP, which regulates cell division in S. pneumoniae. Interestingly, homologues of LocZ are found only in streptococci, lactococci, and enterococci, indicating that this close phylogenetically related group of bacteria evolved a specific solution to spatially regulate cell division.IMPORTANCEBacterial cell division is a highly ordered process regulated in time and space. Recently, we reported that the Ser/Thr protein kinase StkP regulates cell division in Streptococcus pneumoniae, through phosphorylation of several key proteins. Here, we characterized one of the StkP substrates, Spr0334, which we named LocZ. We show that LocZ is a new cell division protein important for proper septum placement and likely functions as a marker of the cell division site. Consistently, LocZ supports proper Z-ring positioning at midcell. LocZ is conserved only among streptococci, lactococci, and enterococci, which lack homologues of the Min and nucleoid occlusion effectors, indicating that these bacteria adapted a unique mechanism to find their middle, reflecting their specific shape and symmetry.

scholarly journals Cooperative ordering of treadmilling filaments in cytoskeletal networks of FtsZ and its crosslinker ZapA

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Paulo Caldas ◽  
Mar López-Pelegrín ◽  
Daniel J. G. Pearce ◽  
Nazmi Burak Budanur ◽  
Jan Brugués ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Large Scale ◽  
Bacterial Cell Division ◽  
Division Site ◽  
Associated Proteins ◽  
Z Ring ◽  
Cytoskeletal Networks ◽  
Cooperative Ordering

AbstractDuring bacterial cell division, the tubulin-homolog FtsZ forms a ring-like structure at the center of the cell. This Z-ring not only organizes the division machinery, but treadmilling of FtsZ filaments was also found to play a key role in distributing proteins at the division site. What regulates the architecture, dynamics and stability of the Z-ring is currently unknown, but FtsZ-associated proteins are known to play an important role. Here, using an in vitro reconstitution approach, we studied how the well-conserved protein ZapA affects FtsZ treadmilling and filament organization into large-scale patterns. Using high-resolution fluorescence microscopy and quantitative image analysis, we found that ZapA cooperatively increases the spatial order of the filament network, but binds only transiently to FtsZ filaments and has no effect on filament length and treadmilling velocity. Together, our data provides a model for how FtsZ-associated proteins can increase the precision and stability of the bacterial cell division machinery in a switch-like manner.

scholarly journals Interaction between Cell Division Proteins FtsE and FtsZ

2007 ◽  
Vol 189 (8) ◽  
pp. 3026-3035 ◽  
Author(s):  
Brian D. Corbin ◽  
Yipeng Wang ◽  
Tushar K. Beuria ◽  
William Margolin
Keyword(s):  
Cell Division ◽  
Abc Transporters ◽  
Fluorescent Protein ◽  
Direct Interaction ◽  
Bacterial Cell Division ◽  
E Coli ◽  
Cell Extracts ◽  
Z Ring ◽  
Green Fluorescent ◽  
Binding Component

ABSTRACT FtsE and FtsX, which are widely conserved homologs of ABC transporters and interact with each other, have important but unknown functions in bacterial cell division. Coimmunoprecipitation of Escherichia coli cell extracts revealed that a functional FLAG-tagged version of FtsE, the putative ATP-binding component, interacts with FtsZ, the bacterial tubulin homolog required to assemble the cytokinetic Z ring and recruit the components of the divisome. This interaction is independent of FtsX, the predicted membrane component of the ABC transporter, which has been shown previously to interact with FtsE. The interaction also occurred independently of FtsA or ZipA, two other E. coli cell division proteins that interact with FtsZ. In addition, FtsZ copurified with FLAG-FtsE. Surprisingly, the conserved C-terminal tail of FtsZ, which interacts with other cell division proteins, such as FtsA and ZipA, was dispensable for interaction with FtsE. In support of a direct interaction with FtsZ, targeting of a green fluorescent protein (GFP)-FtsE fusion to Z rings required FtsZ, but not FtsA. Although GFP-FtsE failed to target Z rings in the absence of ZipA, its localization was restored in the presence of the ftsA* bypass suppressor, indicating that the requirement for ZipA is indirect. Coexpression of FLAG-FtsE and FtsX under certain conditions resulted in efficient formation of minicells, also consistent with an FtsE-FtsZ interaction and with the idea that FtsE and FtsX regulate the activity of the divisome.

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