title: Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase.
abstract: Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Howard
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Nader
authors.initials: N
authors.lastname: Amin
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Benowitz
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Chiarparin
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Cui
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Deng
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Hopkins
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Agnes C L
authors.initials: AC
authors.lastname: Martin
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Frances
authors.initials: F
authors.lastname: Massey
authors.affiliation: GlaxoSmithKline, Infectious Diseases TAU , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mortenson
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Puja
authors.initials: P
authors.lastname: Pathuri
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Tisi
authors.affiliation: Astex Pharmaceuticals Inc., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Williams
keywords: Bacterial DNA ligase; S. aureus; fragment-based drug design; structure-based optimization