title: Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC-MurF): experimental and computational characterization.
abstract: Bacterial resistance to the available antibiotic agents underlines an urgent need for the discovery of novel antibacterial agents. Members of the bacterial Mur ligase family MurC-MurF involved in the intracellular stages of the bacterial peptidoglycan biosynthesis have recently emerged as a collection of attractive targets for novel antibacterial drug design. In this study, we have first extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing a multiple MurC-MurF ligase inhibition for representatives of the extended series of this class. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge, compound 1 represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC-MurF). Subsequent molecular dynamic (MD) simulations coupled with interaction energy calculations were performed for two alternative in silico models of compound 1 in the UMA/D-Glu- and ATP-binding sites of MurD, identifying binding in the ATP-binding site as energetically more favorable in comparison to the UMA/D-Glu-binding site, which was in agreement with steady-state kinetic data. In the final stage, based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives 8-11, exhibiting multiple Mur ligase (MurC-MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for compound 10 it was shown to possess promising antibacterial activity against S. aureus. These compounds represent novel leads that could by further optimization pave the way to novel antibacterial agents.
authors: National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia, andrej.perdih@ki.si.
authors: Andrej
authors: A
authors: Perdih
authors: Martina
authors: M
authors: Hrast
authors: Kaja
authors: K
authors: Pureber
authors: Hélène
authors: H
authors: Barreteau
authors: Simona Golič
authors: SG
authors: Grdadolnik
authors: Darko
authors: D
authors: Kocjan
authors: Stanislav
authors: S
authors: Gobec
authors: Tom
authors: T
authors: Solmajer
authors: Gerhard
authors: G
authors: Wolber
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry*; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D005663:Furans; D000255:Adenosine Triphosphate; D008025:Ligases