title: Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF.
abstract: 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-γ-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 toward effective novel antibacterials.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrast
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Randall
authors.forename: Hélène
authors.initials: H
authors.lastname: Barreteau
authors.forename: Carlos
authors.initials: C
authors.lastname: Contreras-Martel
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
authors.forename: Alex J
authors.initials: AJ
authors.lastname: O'Neill
authors.forename: Dominique
authors.initials: D
authors.lastname: Mengin-Lecreulx
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010457:Peptidoglycan / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D013876:Thiophenes; D010453:Peptide Synthases; C060628:UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase
keywords: 2,6-diaminopimelic acid; Antibacterial agents; Crystal structures; DAP; GlcNAc; MurC; MurD; MurE; MurF; MurF inhibitors; MurNAc; N-acetyl glucosamine; N-acetyl muramic acid; UDP; UDP-N-acetylmuramate:l-Ala ligase; UDP-N-acetylmuramoyl-l-Ala-d-Glu-l-Lys; UDP-N-acetylmuramoyl-l-Ala-d-Glu:meso-DAP ligase or l-Lys; UDP-N-acetylmuramoyl-l-Ala-γ-d-Glu-meso-DAP; UDP-N-acetylmuramoyl-l-Ala-γ-d-Glu-meso-DAP (or l-Lys):d-Ala-d-Ala ligase; UDP-N-acetylmuramoyl-l-Ala:d-Glu ligase; UMtri-l-Lys; UMtri-mDAP; uridine 5′-diphosphate