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Title: Tricyclic GyrB/ParE (TriBE) Inhibitors. A new class of broad-spectrum dual-targeting antibacterial agents

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. 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 seriesmore » demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Moreover, lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.« less
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  1. Trius Therapeutics, San Diego, CA (United States)
  2. ViviSource Labs., Waltham, MA (United States)
  3. MIcromyx LLC., Kalamazoo, MI (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
  5. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 1932-6203
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Additional Journal Information:
Journal Volume: 8; Journal Issue: 12; Journal ID: ISSN 1932-6203
Public Library of Science
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org:
Country of Publication:
United States