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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • Biological Warfare Agents*
  • Cell Line
  • Drug Approval*
  • Drug Evaluation, Preclinical / methods*
  • Female
  • Humans
  • Male
  • Mice
  • United States
  • United States Food and Drug Administration*

Substances

  • Anti-Bacterial Agents
  • Antiviral Agents
  • Biological Warfare Agents

Grant support

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.