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

Leslie W. Tari, Xiaoming Li, Michael Trzoss, Daniel C. Bensen, Zhiyong Chen, Thanh Lam, Junhu Zhang, Suk Joong Lee, Grayson Hough, Doug Phillipson, Suzanne Akers-Rodriguez, Mark L. Cunningham, Bryan P. Kwan, Kirk J. Nelson, Amanda Castellano, Jeff B. Locke, Vickie Brown-Driver, Timothy M. Murphy, Voon S. Ong, Chris M. PillarDean L. Shinabarger, Jay Nix, Felice C Lightstone, Sergio E. Wong, Toan B. Nguyen, Karen J. Shaw, John Finn

Research output: Contribution to journalArticle

57 Scopus citations

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 dualtargeting 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.

Original languageEnglish (US)
Article numbere84409
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Feb 26 2013
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tari, L. W., Li, X., Trzoss, M., Bensen, D. C., Chen, Z., Lam, T., Zhang, J., Lee, S. J., Hough, G., Phillipson, D., Akers-Rodriguez, S., Cunningham, M. L., Kwan, B. P., Nelson, K. J., Castellano, A., Locke, J. B., Brown-Driver, V., Murphy, T. M., Ong, V. S., ... Finn, J. (2013). Tricyclic GyrB/ParE (TriBE) inhibitors: A new class of broad-spectrum dual-targeting antibacterial agents. PLoS One, 8(12), [e84409]. https://doi.org/10.1371/journal.pone.0084409