scholarly journals Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

Antibiotics ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 69 ◽  
Author(s):  
Andrea Casiraghi ◽  
Lorenzo Suigo ◽  
Ermanno Valoti ◽  
Valentina Straniero
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Molecular Mechanisms ◽  
Protein A ◽  
Bactericidal Effect ◽  
Bacterial Cell Division ◽  
Z Ring ◽  
Main Protein ◽  
Ftsz Inhibitors ◽  
Division System

Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.

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.

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 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.

BACTERIAL CELL DIVISION AND THE Z RING

1997 ◽  
Vol 66 (1) ◽  
pp. 93-116 ◽  
Author(s):  
Joe Lutkenhaus and ◽  
S. G. Addinall
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Bacterial Cell Division ◽  
Z Ring

scholarly journals Z-ring membrane anchors associate with cell wall synthases to initiate bacterial cell division

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Manuel Pazos ◽  
Katharina Peters ◽  
Mercedes Casanova ◽  
Pilar Palacios ◽  
Michael VanNieuwenhze ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Division ◽  
Bacterial Cell ◽  
Bacterial Cell Division ◽  
Z Ring

scholarly journals ZapE Is a Novel Cell Division Protein Interacting with FtsZ and Modulating the Z-Ring Dynamics

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Benoit S. Marteyn ◽  
Gouzel Karimova ◽  
Andrew K. Fenton ◽  
Anastasia D. Gazi ◽  
Nicholas West ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Dependent Manner ◽  
Bacterial Cell Division ◽  
Low Oxygen ◽  
Ftsz Ring ◽  
Division Process ◽  
Z Ring ◽  
Cell Division Protein

ABSTRACTBacterial cell division requires the formation of a mature divisome complex positioned at the midcell. The localization of the divisome complex is determined by the correct positioning, assembly, and constriction of the FtsZ ring (Z-ring). Z-ring constriction control remains poorly understood and (to some extent) controversial, probably due to the fact that this phenomenon is transient and controlled by numerous factors. Here, we characterize ZapE, a novel ATPase found in Gram-negative bacteria, which is required for growth under conditions of low oxygen, while loss ofzapEresults in temperature-dependent elongation of cell shape. We found that ZapE is recruited to the Z-ring during late stages of the cell division process and correlates with constriction of the Z-ring. Overexpression or inactivation ofzapEleads to elongation ofEscherichia coliand affects the dynamics of the Z-ring during division.In vitro, ZapE destabilizes FtsZ polymers in an ATP-dependent manner.IMPORTANCEBacterial cell division has mainly been characterizedin vitro. In this report, we could identify ZapE as a novel cell division protein which is not essentialin vitrobut is required during an infectious process. The bacterial cell division process relies on the assembly, positioning, and constriction of FtsZ ring (the so-called Z-ring). Among nonessential cell division proteins recently identified, ZapE is the first in which detection at the Z-ring correlates with its constriction. We demonstrate that ZapE abundance has to be tightly regulated to allow cell division to occur; absence or overexpression of ZapE leads to bacterial filamentation. AszapEis not essential, we speculate that additional Z-ring destabilizing proteins transiently recruited during late cell division process might be identified in the future.

scholarly journals FtsZ assembles the bacterial cell division machinery by a diffusion-and-capture mechanism

2018 ◽  
Author(s):  
Natalia Baranova ◽  
Philipp Radler ◽  
Víctor M. Hernández-Rocamora ◽  
Carlos Alfonso ◽  
Mar López-Pelegrín ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Bacterial Cell Division ◽  
Peptidoglycan Synthesis ◽  
Division Site ◽  
Spatiotemporal Information ◽  
Capture Mechanism ◽  
Z Ring ◽  
Membrane Bound ◽  
Transient Interactions

AbstractThe mechanism of bacterial cell division is largely unknown. The protein machinery performing cell division is organized by FtsZ, a tubulin-homolog that forms treadmilling filaments at the cell division site. Treadmilling is thought to actively move proteins around the cell thereby distributing peptidoglycan synthesis to make two new cell poles. To understand this process, we reconstituted part of the bacterial cell division machinery using the purified components FtsZ, FtsA and truncated transmembrane proteins essential for cell division. We found that membrane-bound cytosolic peptides of FtsN and FtsQ co-migrated with treadmilling FtsZ-FtsA filaments. Remarkably, rather than moving in a directed fashion, individual peptides followed FtsZ filaments by a diffusion-and-capture mechanism. Our work provides a mechanism for how the Z-ring dynamically recruits divisome proteins and highlights the importance of transient interactions for the self-organization of complex biological structures. We propose that this mechanism is used more widely to organize and transmit spatiotemporal information in living cells.One Sentence SummaryFtsZ treadmilling assembles bacterial division machinery by diffusion-and-capture mechanism.

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