Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

Shahila Mehboob, Jinhua Song, Kirk Hevener, Pin Chih Su, Teuta Boci, Libby Brubaker, Lena Truong, Tina Mistry, Jiangping Deng, James L. Cook, Bernard D. Santarsiero, Arun K. Ghosh, Michael E. Johnson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.

Original languageEnglish (US)
Pages (from-to)1292-1296
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number6
DOIs
StatePublished - Mar 15 2015

Fingerprint

Francisella tularensis
Methicillin
Pathogens
Bioactivity
Oxidoreductases
Crystal structure
Anti-Bacterial Agents
Tularemia
Methicillin-Resistant Staphylococcus aureus
Infection
benzimidazole
Lead

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI). / Mehboob, Shahila; Song, Jinhua; Hevener, Kirk; Su, Pin Chih; Boci, Teuta; Brubaker, Libby; Truong, Lena; Mistry, Tina; Deng, Jiangping; Cook, James L.; Santarsiero, Bernard D.; Ghosh, Arun K.; Johnson, Michael E.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 6, 15.03.2015, p. 1292-1296.

Research output: Contribution to journalArticle

Mehboob, S, Song, J, Hevener, K, Su, PC, Boci, T, Brubaker, L, Truong, L, Mistry, T, Deng, J, Cook, JL, Santarsiero, BD, Ghosh, AK & Johnson, ME 2015, 'Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 6, pp. 1292-1296. https://doi.org/10.1016/j.bmcl.2015.01.048
Mehboob, Shahila ; Song, Jinhua ; Hevener, Kirk ; Su, Pin Chih ; Boci, Teuta ; Brubaker, Libby ; Truong, Lena ; Mistry, Tina ; Deng, Jiangping ; Cook, James L. ; Santarsiero, Bernard D. ; Ghosh, Arun K. ; Johnson, Michael E. / Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI). In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 6. pp. 1292-1296.
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