Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction

Sidhartha Chaudhury, Mohamed Diwan M Abdulhameed, Narender Singh, Gregory J. Tawa, Patrik M. D'haeseleer, Adam T. Zemla, Ali Navid, Carol E. Zhou, Matthew C. Franklin, Jonah Cheung, Michael J. Rudolph, James Love, John F. Graf, David A. Rozak, Jennifer L. Dankmeyer, Kei Amemiya, Simon Daefler, Anders Wallqvist

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

In the future, we may be faced with the need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare for this eventuality, our objective was to use a metabolic network-based approach to rapidly identify potential drug targets and prospectively screen and validate novel small-molecule antimicrobials. Our target organism was the fully virulent Francisella tularensis subspecies tularensis Schu S4 strain, a highly infectious intracellular pathogen that is the causative agent of tularemia and is classified as a category A biological agent by the Centers for Disease Control and Prevention. We proceeded with a staggered computational and experimental workflow that used a strain-specific metabolic network model, homology modeling and X-ray crystallography of protein targets, and ligand- and structure-based drug design. Selected compounds were subsequently filtered based on physiological-based pharmacokinetic modeling, and we selected a final set of 40 compounds for experimental validation of antimicrobial activity. We began screening these compounds in whole bacterial cell-based assays in biosafety level 3 facilities in the 20th week of the study and completed the screens within 12 weeks. Six compounds showed significant growth inhibition of F. tularensis, and we determined their respective minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished bacterial growth at 13 μM, with putative activity against pantetheine-phosphate adenylyltransferase, an enzyme involved in the biosynthesis of coenzyme A, encoded by gene coaD. The novel antimicrobial compounds identified in this study serve as starting points for lead optimization, animal testing, and drug development against tularemia. Our integrated in silico/in vitro approach had an overall 15% success rate in terms of active versus tested compounds over an elapsed time period of 32 weeks, from pathogen strain identification to selection and validation of novel antimicrobial compounds.

Original languageEnglish (US)
Article numbere63369
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 21 2013
Externally publishedYes

Fingerprint

Francisella tularensis
Metabolic Networks and Pathways
Tularemia
anti-infective agents
tularemia
drugs
Pathogens
Pharmaceutical Preparations
Workflow
Drug Design
X Ray Crystallography
Biological Factors
Microbial Sensitivity Tests
Coenzyme A
Centers for Disease Control and Prevention (U.S.)
Growth
Disease control
Centers for Disease Control and Prevention
Computer Simulation
biosafety

ASJC Scopus subject areas

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

Cite this

Chaudhury, S., Abdulhameed, M. D. M., Singh, N., Tawa, G. J., D'haeseleer, P. M., Zemla, A. T., ... Wallqvist, A. (2013). Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction. PLoS One, 8(5), [e63369]. https://doi.org/10.1371/journal.pone.0063369

Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction. / Chaudhury, Sidhartha; Abdulhameed, Mohamed Diwan M; Singh, Narender; Tawa, Gregory J.; D'haeseleer, Patrik M.; Zemla, Adam T.; Navid, Ali; Zhou, Carol E.; Franklin, Matthew C.; Cheung, Jonah; Rudolph, Michael J.; Love, James; Graf, John F.; Rozak, David A.; Dankmeyer, Jennifer L.; Amemiya, Kei; Daefler, Simon; Wallqvist, Anders.

In: PLoS One, Vol. 8, No. 5, e63369, 21.05.2013.

Research output: Contribution to journalArticle

Chaudhury, S, Abdulhameed, MDM, Singh, N, Tawa, GJ, D'haeseleer, PM, Zemla, AT, Navid, A, Zhou, CE, Franklin, MC, Cheung, J, Rudolph, MJ, Love, J, Graf, JF, Rozak, DA, Dankmeyer, JL, Amemiya, K, Daefler, S & Wallqvist, A 2013, 'Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction', PLoS One, vol. 8, no. 5, e63369. https://doi.org/10.1371/journal.pone.0063369
Chaudhury S, Abdulhameed MDM, Singh N, Tawa GJ, D'haeseleer PM, Zemla AT et al. Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction. PLoS One. 2013 May 21;8(5). e63369. https://doi.org/10.1371/journal.pone.0063369
Chaudhury, Sidhartha ; Abdulhameed, Mohamed Diwan M ; Singh, Narender ; Tawa, Gregory J. ; D'haeseleer, Patrik M. ; Zemla, Adam T. ; Navid, Ali ; Zhou, Carol E. ; Franklin, Matthew C. ; Cheung, Jonah ; Rudolph, Michael J. ; Love, James ; Graf, John F. ; Rozak, David A. ; Dankmeyer, Jennifer L. ; Amemiya, Kei ; Daefler, Simon ; Wallqvist, Anders. / Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction. In: PLoS One. 2013 ; Vol. 8, No. 5.
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