Synthesis of (-)-viriditoxin: a 6,6'-binaphthopyran-2-one that targets the bacterial cell division protein FtsZ.
Ontology highlight
ABSTRACT:
SUBMITTER: Park YS
PROVIDER: S-EPMC3325170 | biostudies-literature | 2011 Apr
REPOSITORIES: biostudies-literature
Publications
Synthesis of (-)-viriditoxin: a 6,6'-binaphthopyran-2-one that targets the bacterial cell division protein FtsZ.
Park Young Sam YS Grove Charles I CI González-López Marcos M Urgaonkar Sameer S Fettinger James C JC Shaw Jared T JT
Angewandte Chemie (International ed. in English) 20110316 16
Similar Datasets
Project description:A high-yielding and practical synthesis of the bacterial cell division inhibitor PC190723 is described. The synthesis is completed in a longest linear sequence of five steps from commercially available starting materials and can be readily executed on a multigram scale.
| S-EPMC3068231 | biostudies-literature
Project description:The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross-species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3.
| S-EPMC4360151 | biostudies-literature
Project description:The mechanism by which bacteria divide is not well understood. Cell division is mediated by filaments of FtsZ and FtsA (FtsAZ) that recruit septal peptidoglycan-synthesizing enzymes to the division site. To understand how these components coordinate to divide cells, we visualized their movements relative to the dynamics of cell wall synthesis during cytokinesis. We found that the division septum was built at discrete sites that moved around the division plane. FtsAZ filaments treadmilled circumferentially around the division ring and drove the motions of the peptidoglycan-synthesizing enzymes. The FtsZ treadmilling rate controlled both the rate of peptidoglycan synthesis and cell division. Thus, FtsZ treadmilling guides the progressive insertion of new cell wall by building increasingly smaller concentric rings of peptidoglycan to divide the cell.
| S-EPMC5485650 | biostudies-literature
Project description:The key bacterial cell division protein FtsZ can adopt multiple conformations, and prevailing models suggest that transitions of FtsZ subunits from the closed to open state are necessary for filament formation and stability. Using all-atom molecular dynamics simulations, we analyzed state transitions of Staphylococcus aureus FtsZ as a monomer, dimer, and hexamer. We found that monomers can adopt intermediate states but preferentially adopt a closed state that is robust to forced reopening. Dimer subunits transitioned between open and closed states, and dimers with both subunits in the closed state remained highly stable, suggesting that open-state conformations are not necessary for filament formation. Mg2+ strongly stabilized the conformation of GTP-bound subunits and the dimer filament interface. Our hexamer simulations indicate that the plus end subunit preferentially closes and that other subunits can transition between states without affecting inter-subunit stability. We found that rather than being correlated with subunit opening, inter-subunit stability was strongly correlated with catalytic site interactions. By leveraging deep-learning models, we identified key intrasubunit interactions governing state transitions. Our findings suggest a greater range of possible monomer and filament states than previously considered and offer new insights into the nuanced interplay between subunit states and the critical role of nucleotide hydrolysis and Mg2+ in FtsZ filament dynamics.
| S-EPMC11481701 | biostudies-literature
Project description:Biomolecular condensation through phase separation may be a novel mechanism to regulate bacterial processes, including cell division. Previous work revealed that FtsZ, a protein essential for cytokinesis in most bacteria, forms biomolecular condensates with SlmA, a protein that protects the chromosome from damage inflicted by the division machinery in Escherichia coli. The absence of condensates composed solely of FtsZ under the conditions used in that study suggested this mechanism was restricted to nucleoid occlusion by SlmA or to bacteria containing this protein. Here we report that FtsZ alone, under physiologically relevant conditions, can demix into condensates in bulk and when encapsulated in synthetic cell-like systems generated by microfluidics. Condensate assembly depends on FtsZ being in the GDP-bound state and on conditions mimicking the crowded environment of the cytoplasm that promote its oligomerization. Condensates are dynamic and reversibly convert into filaments upon GTP addition. Notably, FtsZ lacking its C-terminal disordered region, a structural element likely to favor biomolecular condensation, also forms condensates, albeit less efficiently. The inherent tendency of FtsZ to form condensates susceptible to modulation by physiological factors, including binding partners, suggests that such mechanisms may play a more general role in bacterial division than initially envisioned.
| S-EPMC8529516 | biostudies-literature
Project description:Forces are important in biological systems for accomplishing key cell functions, such as motility, organelle transport, and cell division. Currently, known force generation mechanisms typically involve motor proteins. In bacterial cells, no known motor proteins are involved in cell division. Instead, a division ring (Z-ring) consists of mostly FtsZ, FtsA, and ZipA is used to exerting a contractile force. The mechanism of force generation in bacterial cell division is unknown. Using computational modeling, we show that Z-ring formation results from the colocalization of FtsZ and FtsA mediated by the favorable alignment of FtsZ polymers. The model predicts that the Z-ring undergoes a condensation transition from a low-density state to a high-density state and generates a sufficient contractile force to achieve division. FtsZ GTP hydrolysis facilitates monomer turnover during the condensation transition, but does not directly generate forces. In vivo fluorescence measurements show that FtsZ density increases during division, in accord with model results. The mechanism is akin to van der Waals picture of gas-liquid condensation, and shows that organisms can exploit microphase transitions to generate mechanical forces.
| S-EPMC2629247 | biostudies-literature
Project description:The study of bacteriophage (phage) gene products and their effects on the host helps to better understand the phage-host relationship and provides clues for the development of new antimicrobial proteins. In this study, we focused on a small protein named Icd with 73 amino acids from phage P1. It inhibits the growth of Escherichia coli and rapidly blocks the formation of Z-ring. The results of bacterial two-hybrid and pull-down experiments showed that Icd directly targets FtsZ, a key protein in bacterial division. Furthermore, we identified the core region of Icd as amino acids 12-51; this 40-amino acid protein had similar antibacterial activity to the full-length Icd, inhibiting bacterial growth and division.
| S-EPMC11897509 | biostudies-literature
Project description:Eight new antimicrobial natural products named chrysophaentins A-H belonging to a new structural class have been isolated from the marine chrysophyte alga Chrysophaeum taylori. Their structures were determined by extensive 2D NMR and MS techniques and are characterized by the presence of two polyhalogenated, polyoxygenated omega,omega'-diarylbutene units connected by two ether bonds to form the suite of macrocyclic natural products. Chrysophaentin A, the most potent of these antibiotics, inhibited the growth of clinically relevant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MIC(50) 1.5 +/- 0.7 microg/mL), multidrug-resistant S. aureus (1.3 +/- 0.4 microg/mL), and vancomycin-resistant Enterococcus faecium (MIC(50) 2.9 +/- 0.8 microg/mL). In vitro enzyme assays and transmission electron microscopy showed chrysophaentin A to inhibit the GTPase activity of the bacterial cytoskeletal protein FtsZ with an IC(50) value of 6.7 +/- 1.7 microg/mL, as well as GTP-induced formation of FtsZ protofilaments. Saturation Transfer Difference (STD) NMR experiments further confirmed chrysophaentin A binds to FtsZ, and NMR competition experiments with GTPgammaS showed chrysophaentin A and GTP to bind competitively to FtsZ. Last, molecular docking simulations provided a low energy model in which chrysophaentin A binds in and occludes a large portion of the GTP binding site of FtsZ in a manner that is consistent with the binding epitope determined by STD NMR.
| S-EPMC2920594 | biostudies-literature
Project description:Nowadays, the emergence of multidrug-resistant bacterial strains initiates the urgent need for the elucidation of the new drug targets for the discovery of antimicrobial drugs. Filamenting temperature-sensitive mutant Z (FtsZ), a eukaryotic tubulin homolog, is a GTP-dependent prokaryotic cytoskeletal protein and is conserved among most bacterial strains. In vitro studies revealed that FtsZ self-assembles into dynamic protofilaments or bundles and forms a dynamic Z-ring at the center of the cell in vivo, leading to septation and consequent cell division. Speculations on the ability of FtsZ in the blockage of cell division make 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 in the properties of FtsZ protein and bacterial cell division, as well as in the development of FtsZ inhibitors.
| S-EPMC7416170 | biostudies-literature
Project description:The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of -140° to -90° for all investigated compounds. The corresponding ensemble average of the coupling constants (3) J(C4,H1') is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution.
| S-EPMC2975913 | biostudies-literature