Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF
Hrast, Martina (Author), Turk, Samo (Author), Sosič, Izidor (Author), Knez, Damijan (Author), Randall, Christopher P. (Author), Barreteau, Hélène (Author), Contreras-Martel, Carlos (Author), Dessen, Andréa (Author), O'Neill, Alex J. (Author), Mengin-Lecreulx, Dominique (Author), Blanot, Didier (Author), Gobec, Stanislav (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0223523413003139 This link opens in a new window

Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of d-Ala-d-Ala to the nucleotide precursor UDP-MurNAc-l-Ala-Ž-d-Glu-meso-DAP (or l-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization towards effective novel antibacterials.

Keywords:MurF inhibitorji, protivnetne učinkovine, kristalne strukture, Mur ligaze
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:str. 32-45
Numbering:Vol. 66
ISSN on article:0223-5234
DOI:10.1016/j.ejmech.2013.05.013 Link is opened in a new window
COBISS.SI-ID:3452785 Link is opened in a new window
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Record is a part of a journal

Title:European journal of medicinal chemistry
Shortened title:Eur. j. med. chem.
COBISS.SI-ID:25429760 This link opens in a new window

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