The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

Andreu, José Manuel; Schaffner-Barbero, Claudia; Huecas, Sonia; Alonso, Dulce; López-Rodrı́guez, Marı́a L.; Ruiz-Avila, Laura B.; Núñez-Ramírez, Rafael; Llorca, Óscar; Martín-Galiano, Antonio J.

doi:10.1074/jbc.m109.094722

Cited by 156 publications

(216 citation statements)

References 51 publications

(61 reference statements)

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“…Both sets of mutants (Mj-group E and Sa-resistant), although not completely coincident, delineate the long cleft between the C-domain and H7, which is in a position equivalent to the taxol binding site of tubulin. PC190723 is a polymer-stabilizing agent for Bs-FtsZ and Sa-FtsZ (9). It is to be investigated whether this compound, by binding to said cleft, interferes with the curved-straight switching in Bs-FtsZ and Sa-FtsZ, similarly to what taxanes do for tubulin by favoring its assembled straight form (65,66).…”

Section: Ftsz Monomer Flexibility and Predicted Subdomain Movements Mmentioning

confidence: 99%

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Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches

Martín-Galiano

Buey

Cabezas

et al. 2010

Journal of Biological Chemistry

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The molecular switch for nucleotide-regulated assembly and disassembly of the main prokaryotic cell division protein FtsZ is unknown despite the numerous crystal structures that are available. We have characterized the functional motions in FtsZ with a computational consensus of essential dynamics, structural comparisons, sequence conservation, and networks of co-evolving residues. Employing this information, we have constructed 17 mutants, which alter the FtsZ functional cycle at different stages, to modify FtsZ flexibility. The mutant phenotypes ranged from benign to total inactivation and included increased GTPase, reduced assembly, and stabilized assembly. Six mutations clustering at the long cleft between the C-terminal ␤-sheet and core helix H7 deviated FtsZ assembly into curved filaments with inhibited GTPase, which still polymerize cooperatively. These mutations may perturb the predicted closure of the C-terminal domain onto H7 required for switching between curved and straight association modes and for GTPase activation. By mapping the FtsZ assembly switch, this work also gives insight into FtsZ druggability because the curved mutations delineate the putative binding site of the promising antibacterial FtsZ inhibitor PC190723.

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Section: Ftsz Monomer Flexibility and Predicted Subdomain Movements Mmentioning

confidence: 99%

“…GTP analogs substituted at C8 selectively inhibit purified FtsZ while supporting tubulin assembly (7). FtsZ has been validated as the target of an effective bactericidal compound PC190723 (8), which is an FtsZ polymer-stabilizing agent (9).…”

mentioning

confidence: 99%

Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches

Martín-Galiano

Buey

Cabezas

et al. 2010

Journal of Biological Chemistry

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“…Nevertheless, thiostrepton for IF-2, pulvomycin and GE2270A for EF-Tu, and PC190723, Berberine and Zantrins for FtsZ have been exploited and investigated for their inhibitory activity towards those GTPases. [29][30][31][32][33][34][35][36][37][38] The recent technological advances in computational modeling of protein structures have a crucial role in drug design and its retrieval. In our study, structure-based pharmacophore design screened a relatively small number of candidate molecules and we successfully identified three inhibitors (SBI-34462, -34566, and -34612) for an essential bacterial GTPase Der that has been unexploited for antibacterial target.…”

Section: Models Of Der Gtpase Complexes With Bioactive Compoundsmentioning

confidence: 99%

Structure-based design and screening of inhibitors for an essential bacterial GTPase, Der

Hwang

Tseitin²,

Ramnarayan³

et al. 2012

J Antibiot

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Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg 2+ concentration. As Der is an essential and ubiquitous protein in bacteria, it may prove to be an ideal cellular target against which new antibiotics can be developed. In the present study, we describe our attempts to identify novel antibiotics specifically targeting Der GTPase. We performed the structure-based design of Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der (TmDer). Virtual screening of commercially available chemical library retrieved 257 small molecules that potentially inhibit Der GTPase activity. These 257 chemicals were tested for their in vitro effects on TmDer GTPase and in vivo antibacterial activities. We identified three structurally diverse compounds, SBI-34462, -34566 and -34612, that are both biologically active against bacterial cells and putative enzymatic inhibitors of Der GTPase homologs. We also presented the possible interactions of each compound with the Der GTP-binding site to understand the mechanism of inhibition. Therefore, our lead compounds inhibiting Der GTPase provide scaffolds for the development of novel antibiotics against antibiotic-resistant pathogenic bacteria.

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“…Andreu and coworkers found that PC190723 inhibited GTPase activity of B. subtilis FtsZ through inducing FtsZ polymers into straight bundles and ribbons. The result suggested that PC190723 inhibit FtsZ via the stabilization of the FtsZ polymerization [92]. Lumb and co-workers also conducted some structural and biochemical analyses of S. aureus FtsZ with PC190723.…”

Section: Dichamanetin and Its Derivativementioning

confidence: 99%

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

Sun¹,

Wong²

2018

Fighting Antimicrobial Resistance

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The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

Abstract: It is yet to be investigated whether both ligands target structurally related assembly switches.

Cited by 156 publications

References 51 publications

Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches

Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches

Structure-based design and screening of inhibitors for an essential bacterial GTPase, Der

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

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