A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

Peter B. Madrid, Sidharth Chopra, Ian D. Manger, Lynne Gilfillan, Tiffany R. Keepers, Amy C. Shurtleff, Carol E. Green, Lalitha V. Iyer, Holli Hutcheson Dilks, Robert A. Davey, Andrey A. Kolokoltsov, Ricardo Carrion, Jean L. Patterson, Sina Bavari, Rekha G. Panchal, Travis K. Warren, Jay B. Wells, Walter H. Moos, RaeLyn L. Burke, Mary J. Tanga

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

Background: The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings: A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance: The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

Original languageEnglish (US)
Article numbere60579
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 5 2013
Externally publishedYes

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Biological Factors
Viruses
Drug Repositioning
Bacillus anthracis
drugs
Pharmaceutical Preparations
viruses
Lassa Fever
Lassa virus
Ebolavirus
Pathogens
Bacilli
Francisella tularensis
Coxiella burnetii
Assays
Chloroquine
Erythromycin
Antiviral Agents
chloroquine
Emergencies

ASJC Scopus subject areas

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

Cite this

Madrid, P. B., Chopra, S., Manger, I. D., Gilfillan, L., Keepers, T. R., Shurtleff, A. C., ... Tanga, M. J. (2013). A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents. PLoS One, 8(4), [e60579]. https://doi.org/10.1371/journal.pone.0060579

A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents. / Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

In: PLoS One, Vol. 8, No. 4, e60579, 05.04.2013.

Research output: Contribution to journalArticle

Madrid, PB, Chopra, S, Manger, ID, Gilfillan, L, Keepers, TR, Shurtleff, AC, Green, CE, Iyer, LV, Dilks, HH, Davey, RA, Kolokoltsov, AA, Carrion, R, Patterson, JL, Bavari, S, Panchal, RG, Warren, TK, Wells, JB, Moos, WH, Burke, RL & Tanga, MJ 2013, 'A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents', PLoS One, vol. 8, no. 4, e60579. https://doi.org/10.1371/journal.pone.0060579
Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC et al. A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents. PLoS One. 2013 Apr 5;8(4). e60579. https://doi.org/10.1371/journal.pone.0060579
Madrid, Peter B. ; Chopra, Sidharth ; Manger, Ian D. ; Gilfillan, Lynne ; Keepers, Tiffany R. ; Shurtleff, Amy C. ; Green, Carol E. ; Iyer, Lalitha V. ; Dilks, Holli Hutcheson ; Davey, Robert A. ; Kolokoltsov, Andrey A. ; Carrion, Ricardo ; Patterson, Jean L. ; Bavari, Sina ; Panchal, Rekha G. ; Warren, Travis K. ; Wells, Jay B. ; Moos, Walter H. ; Burke, RaeLyn L. ; Tanga, Mary J. / A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents. In: PLoS One. 2013 ; Vol. 8, No. 4.
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