title: Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF).
abstract: Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family-MurC, MurD, MurE and MurF-are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park's nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC-MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC-MurF enzymes in biochemical inhibition assays and molecules 10-14 containing benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC-MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents.
authors: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia; Institute of Pharmacy, Freie Universität Berlin, Königin Luise-Strasse 2+4, 14195 Berlin, Germany. Electronic address: andrej.perdih@ki.si.
authors: Andrej
authors: A
authors: Perdih
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1001 Ljubljana, Slovenia.
authors: Martina
authors: M
authors: Hrast
authors: Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, Univ Paris-Sud, 91405 Orsay, France.
authors: Hélène
authors: H
authors: Barreteau
authors: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1001 Ljubljana, Slovenia.
authors: Stanislav
authors: S
authors: Gobec
authors: Institute of Pharmacy, Freie Universität Berlin, Königin Luise-Strasse 2+4, 14195 Berlin, Germany.
authors: Gerhard
authors: G
authors: Wolber
authors: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors: Tom
authors: T
authors: Solmajer
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D011758:Pyrroles; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase; C067286:2,5-dimethylpyrrole
keywords: Antibacterial agents; Bacterial Mur (MurC–MurF) ligase; Drug design; Linear Interaction Energy (LIE) method; Molecular docking; Molecular dynamics (MD); Structure-based pharmacophores; Virtual screening