title: Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.
abstract: Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Trzoss
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bensen
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Junhu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Suk Joong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Grayson
authors.initials: G
authors.lastname: Hough
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Doug
authors.initials: D
authors.lastname: Phillipson
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Akers-Rodriguez
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cunningham
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Kwan
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Nelson
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Castellano
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Jeff B
authors.initials: JB
authors.lastname: Locke
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Vickie
authors.initials: V
authors.lastname: Brown-Driver
authors.affiliation: ViviSource Laboratories, Waltham.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Murphy
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Voon S
authors.initials: VS
authors.lastname: Ong
authors.affiliation: Micromyx LLC, Kalamazoo, Michigan, United States of America.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Pillar
authors.affiliation: Micromyx LLC, Kalamazoo, Michigan, United States of America.
authors.forename: Dean L
authors.initials: DL
authors.lastname: Shinabarger
authors.affiliation: Advanced Light Source, Beamline 4.2.2, Berkeley, California, United States of America.
authors.forename: Jay
authors.initials: J
authors.lastname: Nix
authors.affiliation: Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Livermore, California, United States of America.
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
authors.affiliation: Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Livermore, California, United States of America.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Wong
authors.affiliation: Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Livermore, California, United States of America.
authors.forename: Toan B
authors.initials: TB
authors.lastname: Nguyen
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Shaw
authors.affiliation: Trius Therapeutics, San Diego, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Finn
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase