title: Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
abstract: In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes.
authors.affiliation: Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States. Electronic address: kerry.benenato@astrazeneca.com.
authors.forename: Kerry
authors.initials: K
authors.lastname: Murphy-Benenato
authors.affiliation: Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Hongming
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.affiliation: Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Hajnalka E
authors.initials: HE
authors.lastname: Davis
authors.affiliation: Department of Bioscience, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Bioscience, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: D Bryan
authors.initials: DB
authors.lastname: Prince
authors.affiliation: Department of Bioscience, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Haris
authors.initials: H
authors.lastname: Jahic
authors.affiliation: Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Stokes
authors.affiliation: Department of Bioscience, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
mesh_terms: D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011088:DNA Ligases; C120640:DNA ligase (NAD)
keywords: Adenosine; Antibacterial; NAD(+)-dependent ligase; Resistance; Thienopyridine