Bithionol blocks pathogenicity of bacterial toxins, ricin, and Zika virus.

William Leonardi,Tara Kenny,Sina Bavari,Michael C Bassik,Robert Manasherob,Andrew D Haddow,Farooq Nasar,Amy Li,Jeffrey H Elliott,Mikhail Martchenko,Kseniya Polukhina,Stanley N Cohen,Veronica Soloveva,Leeor Zilbermintz,Rouzbeh Zamani,Anastasia Levitin,Luisa W Cheng,Dima N Gharaibeh ,Sharon Tran ,Xiangyang Chi ,J Zozaya

doi:10.1038/srep34475

Abstract

Diverse pathogenic agents often utilize overlapping host networks, and hub proteins within these networks represent attractive targets for broad-spectrum drugs. Using bacterial toxins, we describe a new approach for discovering broad-spectrum therapies capable of inhibiting host proteins that mediate multiple pathogenic pathways. This approach can be widely used, as it combines genetic-based target identification with cell survival-based and protein function-based multiplex drug screens, and concurrently discovers therapeutic compounds and their protein targets. Using B-lymphoblastoid cells derived from the HapMap Project cohort of persons of African, European, and Asian ancestry we identified host caspases as hub proteins that mediate the lethality of multiple pathogenic agents. We discovered that an approved drug, Bithionol, inhibits host caspases and also reduces the detrimental effects of anthrax lethal toxin, diphtheria toxin, cholera toxin, Pseudomonas aeruginosa exotoxin A, Botulinum neurotoxin, ricin, and Zika virus. Our study reveals the practicality of identifying host proteins that mediate multiple disease pathways and discovering broad-spectrum therapies that target these hub proteins.

Highlights

Diverse pathogenic agents often utilize overlapping host networks, and hub proteins within these networks represent attractive targets for broad-spectrum drugs
Diphtheria, and Botulinum toxins reach the cytoplasm from acidified endosomes, cholera, Pseudomonas aeruginosa and ricin toxins are transported into the cytoplasm through the host ER-associated degradation pathway[4]
Using one of those toxins, Pseudomonas aeruginosa exotoxin A (PE), we set out to identify such hub proteins by i) determining whether known genetic mutations in host proteins exploited by PE affect the sensitivity of host cells to this toxin, and ii) investigating whether these host proteins are exploited by additional pathogenic agents

Summary

Introduction

Diverse pathogenic agents often utilize overlapping host networks, and hub proteins within these networks represent attractive targets for broad-spectrum drugs. The availability of human B-cells, which are physiological targets of PE7 through the HapMap Project[8] has provided us with an opportunity to test whether mutations in host proteins that constitute the PE pathogenicity pathway affect the cellular sensitivity to this toxin. These results show that the activity of caspases affects host cell sensitivity to toxins, and that these proteins are potential therapeutic intervention points and targets for the following drug screens.

Results

Conclusion