Faculty Opinions recommendation of Spatial regulators for bacterial cell division self-organize into surface waves in vitro.

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.

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Analysis of degradation of bacterial cell division protein FtsZ by the ATP-dependent zinc-metalloprotease FtsH in vitro

Microbiological Research ◽

10.1016/j.micres.2006.03.001 ◽

2008 ◽

Vol 163 (1) ◽

pp. 21-30 ◽

Cited By ~ 5

Author(s):

Ramanujam Srinivasan ◽

Haryadi Rajeswari ◽

Parthasarathi Ajitkumar

Keyword(s):

Cell Division ◽

Bacterial Cell ◽

Bacterial Cell Division ◽

Zinc Metalloprotease ◽

Cell Division Protein

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

Nature Communications ◽

10.1038/s41467-019-13702-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 17

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.

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

mBio ◽

10.1128/mbio.00022-14 ◽

2014 ◽

Vol 5 (2) ◽

Cited By ~ 23

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.

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Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03781-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 914-922 ◽

Cited By ~ 16

Author(s):

Jingru Meng ◽

Fei Da ◽

Xue Ma ◽

Ning Wang ◽

Yukun Wang ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Cell Division ◽

Nucleic Acid ◽

Bacterial Cell ◽

Locked Nucleic Acid ◽

Bacterial Cell Division ◽

Inhibitory Effects ◽

Content Type ◽

Division Process

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) infections are becoming increasingly difficult to treat, owing to acquired antibiotic resistance. The emergence and spread of MRSA limit therapeutic options and require new therapeutic strategies, including novel MRSA-active antibiotics. Filamentous temperature-sensitive protein Z (FtsZ) is a highly conserved bacterial tubulin homologue that is essential for controlling the bacterial cell division process in different species ofS. aureus. We conjugated a locked nucleic acid (LNA) that targetedftsZmRNA with the peptide (KFF)3K, to generate peptide-LNA (PLNA). The present study aimed to investigate whether PLNA could be used as a novel antibacterial agent. PLNA787, the most active agent synthesized, exhibited promising inhibitory effects on four pathogenicS. aureusstrainsin vitro. PLNA787 inhibited bacterial growth and resolved lethal Mu50 infections in epithelial cell cultures. PLNA787 also improved the survival rates of Mu50-infected mice and was associated with reductions of bacterial titers in several tissue types. The inhibitory effects onftsZmRNA and FtsZ protein expression and inhibition of the bacterial cell division process are considered to be the major mechanisms of PLNA. PLNA787 demonstrated activity against MRSA infectionsin vitroandin vivo. Our findings suggest thatftsZmRNA is a promising new target for developing novel antisense antibiotics.

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A Novel Z-Ring Associated Protein ZapA-Like Protein (PA5407) From Pseudomonas aeruginosa Promotes FtsZ to Form Double Filaments

Frontiers in Microbiology ◽

10.3389/fmicb.2021.717013 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoyu Wang ◽

Xueqin Ma ◽

Zhe Li ◽

Mingyue Niu ◽

Meiting Zhai ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Cell Division ◽

Bacterial Cell ◽

Regulatory Protein ◽

Ring Structure ◽

Bacterial Cell Division ◽

Bacterial Division ◽

Z Ring ◽

Almost All

Bacterial cell division is initiated by the assembly of the contraction ring (Z-ring), which consists of the self-assembled FtsZ protofilaments and dozens of other associate proteins. ZapA, a regulatory protein found in almost all bacteria, stabilizes FtsZ protofilaments to form bundles and enhances the Z-ring condensation. Here, we reported that another small protein from Pseudomonas aeruginosa, ZapA-Like protein (ZapAL; PA5407), is a new FtsZ associated protein. ZapAL exists in many Pseudomonas species and shares only 20% sequence identity to ZapA. ZapAL interacts with FtsZ and induces FtsZ to form long straight double filaments; in comparison, ZapA promotes long bundles with multiple FtsZ filaments. ZapAL has only a mild effect on GTPase activity of FtsZ, which is reduced by around 26% when 10 μM ZapAL is added in the solution. However, to study their assembly dynamics using light-scattering assay, we found that FtsZ-ZapAL double filament is stable and no depolymerization process is observed, which is different from ZapA. Further research found that ZapA and ZapL are likely to form heterodimers. The bundles formed by the mixture of FtsZ-ZapA-ZapAL will depolymerize after GTP is hydrolyzed. Consistent with ZapAL interaction with FtsZ in vitro, the expression of ZapAL-GFP was observed as a narrow band or spots in the middle of the cells, suggesting that it is a component of bacterial division machinery. Similar to ZapA, ZapAL is also not essential for bacterial cell division. Little changes were observed when zapAL gene was deleted, or overexpressed under normal conditions; however, overexpression of ZapAL caused zapA-deficient cells to grow approximately two times longer, showing a mild bacterial division defect. Although we still do not know the exact physiological roles of ZapAL, our results suggest that ZapAL is a novel Z-ring associate protein, which may work together with ZapA to stabilize the FtsZ protofilament and Z-ring structure.

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