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. 2013;8(4):e60579.
doi: 10.1371/journal.pone.0060579. Epub 2013 Apr 5.

A systematic screen of FDA-approved drugs for inhibitors of biological threat agents

Peter B Madrid  1 , 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 Jr, Jean L Patterson, Sina Bavari, Rekha G Panchal, Travis K Warren, Jay B Wells, Walter H Moos, Raelyn L Burke, Mary J Tanga
Affiliations

A systematic screen of FDA-approved drugs for inhibitors of biological threat agents

Peter B Madrid et al. PLoS One. 2013.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Schematic diagram of the drug-repurposing screen.
Figure 2
Figure 2. Venn diagram showing overlap of unique intracellularly active antibacterial and antiviral hits.
The drugs common between BA and FT include Clindamycin, Dirithromycin, Erythromycin Ethylsuccinate, Gemifloxacin, Lomefloxacin, Minocycline, Norfloxacin, Oxytetracycline and Tetracycline. Drugs in common between BA and CB include Erythromycin ethylsuccinate, Lomefloxacin and Netilmicin. The drugs in common between CB and FT include Erythromycin ethylsuccinate and Lomefloxacin. The common drugs between EBOV and MARV include Amlopidine, Amidiaquine, Biperiden, Carprofen, Chloroquine, Dexbrompheniramine, Dibucaine, Diphenoxylate, Diphenylpyraline, Dipivefrin, Dirithromycin, Estradiol propionate, Fluoxentine, Ketotifen, Levopropoxyphene, Mycophenolate mofetil, Oxyphencyclimine, Paroxentine, Penbutolol, Prochlorperazine, Protriptyline, Toremifene and Trihexyphenidyl. Only Chloroquine and Diphenoxylate were common between LASV and EBOV and between LASV and MARV.
Figure 3
Figure 3. BA in vivo inhibitor efficacy screen.
The antibiotics are represented by the following symbols: Lomefloxacin, 85 mg/kg (blue diamond); Clarithromycin, 500 mg/kg (red square); Erythromycin, 500 mg/kg (green triangle); Norfloxacin, 170 mg/kg (purple cross); Clindamycin, 500 mg/kg (teal cross); Tetracycline, 425 mg/kg (orange circle); Erythromycin ethylsuccinate, 500 mg/kg (light blue gray line); Minocycline, 500 mg/kg (mauve line); Dirithromycin, 500 mg/kg (light green line) and the vehicle (light purple triangle).
Figure 4
Figure 4. EBOV in vivo inhibitor efficacy screen.
The antivirals are represented by the following symbols: Prochlorperazine (blue diamond); Chloroquine, 90 mg/kg (red square); Dirithromcyin, 50 mg/kg (green triangle); Erythromycin ethylsuccinate, 75 mg/kg (purple cross); Amlodipine, 10 mg/kg (blue cross); Fluoxentine, 20 mg/kg (orange circle); Penbutolol, 25 mg/kg (light blue-gray line) and the vehicle (mauve line).
Figure 5
Figure 5. Repeat-dose pharmacokinetics of CQ in male Balb/c mice.
CQ was administered in two dose regimens: i) single dose at 90 mg/kg, IP, and ii) twice daily repeat dose at 90 mg/kg, IP, for a period of 8 days. Full pharmacokinetic profiling was performed after the single dose administration, while sampling was performed after repeat dose administration at 30 min prior to and 4 h after the first dose on Days 2, 4, 6 and 8.
Figure 6
Figure 6. Co-localization of virus particles with endosomal markers.
Cells were incubated with fluorescently labeled virus particles (green) for 3 h. Cells were either untreated or pretreated with 50 µM CQ for 1 h before addition of and then during incubation with virus. After the incubation period cells were fixed and stained with EEA1 or LAMP1 reactive antibodies and corresponding secondary antibody (red). Cells were then stained with DAPI to visualize cell nuclei (blue) and were imaged by confocal microscopy. Arrowheads indicate representative virus particles co-localized with each endosomal marker.
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References

    1. Kuhn JH, Dodd LE, Wahl-Jensen V, Radoshitzky SR, Bavari S, et al. (2011) Evaluation of perceived threat differences posed by filovirus variants. Biosecur Bioterror 9: 361–371. - PMC - PubMed
    1. Center for Disease Control and Prevention (2013) Bioterrorism Agents/Diseases. Center for Disease Control and Prevention. Available: http://www.bt.cdc.gov/agent/agentlist-category.asp: Accessed 10 Feb 2013.
    1. Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, Ascher MS, et al. (2002) Anthrax as a biological weapon, 2002: Updated recommendations for management. JAMA 287: 2236–2252. - PubMed
    1. Center for Disease Control and Prevention (2012) Anthrax. Available: http://emergency.cdc.gov/agent/anthrax/: Accessed 29 Feb 2012.
    1. Ellis J, Oyston PC, Green M, Titball RW (2002) Tularemia. Clin Microbiol Rev 15: 631–646. - PMC - PubMed

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Grants and funding

This work was supported by the Defense Threat Reduction Agency contract HDTRA1-07-C-0083 and internal grants of SRI International. The views expressed in this publication are those of the authors and not necessarily those of the funding organization. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.