Abstract
A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.
Highlights
In a systematic effort to identify candidates for repurposing drugs as broad-spectrum, host-oriented, anti-toxin countermeasures, we screened members of the Johns Hopkins Clinical Compound Library (JHCCL)[3] of 1,581 agents previously approved as drugs by the US Food and Drug Administration for the ability to reduce lethality of RAW264.7 and C32 cells treated either with Bacillus anthracis lethal toxin or diphtheria toxin (Fig. 1a)
While we observed high levels of caspase-1 activity upon lethal factor (LF)-protective antigen (PA) treatment in the absence of AQ, active caspase-1 was not detected in AQ-treated cells that were challenged with anthrax toxin (Fig. 3a)
We have shown that AQ is a broad-spectrum drug that could be applied rapidly to cure biological emergencies caused by the several identified pathogens (Fig. 5)
Summary
Two anti-malarial drugs, Chloroquine (CQ) and Amodiaquine (AQ), were observed to completely protect host cells against anthrax toxin killing in 6-hours toxin killing assay (Fig. 2a). While we observed high levels of caspase-1 activity upon LF-PA treatment in the absence of AQ, active caspase-1 was not detected in AQ-treated cells that were challenged with anthrax toxin (Fig. 3a).
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