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

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. In the bacterial FASII pathway we found it 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. Furthermore, 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). Finally, 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.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [3];  [4];  [4];  [3];  [2];  [1]
  1. Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology; Novalex Therapeutics, Chicago, IL (United States)
  2. Purdue Univ., West Lafayette, IN (United States). Dept. of Chemistry and Dept. of Medicinal Chemistry
  3. Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology
  4. Loyola Univ. Chicago, Maywood, IL (United States). Division of Infectious Diseases; Edward Hines Jr. VA Hospital, Hines, IL (United States)
Publication Date:
Research Org.:
Univ. of Illinois, Chicago, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
OSTI Identifier:
1344120
Alternate Identifier(s):
OSTI ID: 1252342
Grant/Contract Number:  
AC02-06CH11357; U01-AI077949; R41AI110090; UL1TR000050; P41-GM103311; 085P1000817
Resource Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 25; Journal Issue: 6; Journal ID: ISSN 0960-894X
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Enoyl reductase; Benzimidazole scaffold; F. tularensis; FabI inhibitor; S. aureus; MRSA

Citation Formats

Mehboob, Shahila, Song, Jinhua, Hevener, Kirk E., Su, Pin-Chih, Boci, Teuta, Brubaker, Libby, Truong, Lena, Mistry, Tina, Deng, Jiangping, Cook, James L., Santarsiero, Bernard D., Ghosh, Arun K., and Johnson, Michael E. Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI). United States: N. p., 2015. Web. doi:10.1016/j.bmcl.2015.01.048.
Mehboob, Shahila, Song, Jinhua, Hevener, Kirk E., 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). United States. https://doi.org/10.1016/j.bmcl.2015.01.048
Mehboob, Shahila, Song, Jinhua, Hevener, Kirk E., Su, Pin-Chih, Boci, Teuta, Brubaker, Libby, Truong, Lena, Mistry, Tina, Deng, Jiangping, Cook, James L., Santarsiero, Bernard D., Ghosh, Arun K., and Johnson, Michael E. Thu . "Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)". United States. https://doi.org/10.1016/j.bmcl.2015.01.048. https://www.osti.gov/servlets/purl/1344120.
@article{osti_1344120,
title = {Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)},
author = {Mehboob, Shahila and Song, Jinhua and Hevener, Kirk E. and Su, Pin-Chih and Boci, Teuta and Brubaker, Libby and Truong, Lena and Mistry, Tina and Deng, Jiangping and Cook, James L. and Santarsiero, Bernard D. and Ghosh, Arun K. and Johnson, Michael E.},
abstractNote = {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. In the bacterial FASII pathway we found it 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. Furthermore, 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). Finally, 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.},
doi = {10.1016/j.bmcl.2015.01.048},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 6,
volume = 25,
place = {United States},
year = {Thu Jan 29 00:00:00 EST 2015},
month = {Thu Jan 29 00:00:00 EST 2015}
}

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Cited by: 16 works
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Works referencing / citing this record:

Comparison of radii sets, entropy, QM methods, and sampling on MM-PBSA, MM-GBSA, and QM/MM-GBSA ligand binding energies of F . tularensis enoyl-ACP reductase (FabI)
journal, July 2015

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  • Journal of Computational Chemistry, Vol. 36, Issue 25
  • DOI: 10.1002/jcc.24011

Structure‐based drug design and in vitro testing reveal new inhibitors of enoyl‐acyl carrier protein reductases
journal, June 2019

  • Ghattas, Mohammad A.; Eissa, Nermin A.; Tessaro, Francesca
  • Chemical Biology & Drug Design
  • DOI: 10.1111/cbdd.13536

Antimicrobial potential of 1H-benzo[d]imidazole scaffold: a review
journal, February 2019


Antimicrobial potential of 1H-benzo[d]imidazole scaffold: a review
journal, February 2019