izpis_h1_title_alt

6-arylpyrido[2,3-d]pyrimidines as novel ATP-competitive inhibitors of bacterial D-alanine: D-alanine ligase
Škedelj, Veronika (Avtor), Arsovska, Emilija (Avtor), Tomašič, Tihomir (Avtor), Kroflič, Ana (Avtor), Hodnik, Vesna (Avtor), Hrast, Martina (Avtor), Bešter-Rogač, Marija (Avtor), Anderluh, Gregor (Avtor), Gobec, Stanislav (Avtor), Bostock, Julieanne M. (Avtor), Chopra, Ian (Avtor), O'Neill, Alex (Avtor), Randall, Christopher P. (Avtor), Zega, Anamarija (Avtor)

URLURL - Predstavitvena datoteka, za dostop obiščite http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039922 Povezava se odpre v novem oknu

Izvleček
Background: ATP-dependent D-alanine:D-alanine ligase (Ddl) is a part of biochemical machinery involved in peptidoglycan biosynthesis, as it catalyzes the formation of the terminal D-ala-D-ala dipeptide of the peptidoglycan precursor UDPMurNAc pentapeptide. Inhibition of Ddl prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search of novel effective antimicrobial drugs. To address the problem of a relentless increase in resistance to known antimicrobial agents we focused our attention to discovery of novel ATP-competitive inhibitors of Ddl. Methodology/Principal Findings: Encouraged by recent successful attempts to find selective ATP-competitive inhibitors of bacterial enzymes we designed, synthesized and evaluated a library of 6-arylpyrido[2,3-d]pyrimidine-based compounds as inhibitors of Escherichia coli DdlB. Inhibitor binding to the target enzyme was subsequently confirmed by surface plasmon resonance and studied with isothermal titration calorimetry. Since kinetic analysis indicated that 6-arylpyrido[2,3- d]pyrimidines compete with the enzyme substrate ATP, inhibitor binding to the ATP-binding site was additionally studied with docking. Some of these inhibitors were found to possess antibacterial activity against membrane-compromised and efflux pump-deficient strains of E. coli. Conclusions/Significance: We discovered new ATP-competitive inhibitors of DdlB, which may serve as a starting point for development of more potent inhibitors of DdlB that could include both, an ATP-competitive and D-Ala competitive moiety.

Jezik:Angleški jezik
Ključne besede:D-alanin ligaze, bakterijska odpornost, Ddl inhibitorji, antibiotiki, sinteza
Vrsta gradiva:Delo ni kategorizirano (r6)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2012
Št. strani:str. e39922-1-e39922-14
Številčenje:Vol. 7, no. 8
UDK:547.9.057:615.2
ISSN pri članku:1932-6203
COBISS.SI-ID:3286897 Povezava se odpre v novem oknu
Število ogledov:661
Število prenosov:244
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
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Naslov:PloS one
Založnik:Public Library of Science
ISSN:1932-6203
COBISS.SI-ID:2005896 Povezava se odpre v novem oknu

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