Bithionol blocks pathogenicity of bacterial toxins, ricin, and Zika virus.
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.
Keck Graduate Institute, Claremont, CA 91711, USA.
William
W
Leonardi
Keck Graduate Institute, Claremont, CA 91711, USA.
Leeor
L
Zilbermintz
Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, United States Department of Agriculture (USDA), Albany, CA 94710, USA.
Luisa W
LW
Cheng
Keck Graduate Institute, Claremont, CA 91711, USA.
Josue
J
Zozaya
Keck Graduate Institute, Claremont, CA 91711, USA.
Sharon H
SH
Tran
Keck Graduate Institute, Claremont, CA 91711, USA.
Jeffrey H
JH
Elliott
Keck Graduate Institute, Claremont, CA 91711, USA.
Kseniya
K
Polukhina
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Robert
R
Manasherob
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Amy
A
Li
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Xiaoli
X
Chi
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Dima
D
Gharaibeh
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Tara
T
Kenny
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Rouzbeh
R
Zamani
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.|Henry M. Jackson Foundation, Bethesda, MD, 20817, USA.|Biotechnology High Performance Computing Software Applications Institute (BHSAI), Frederick, MD, 21702, USA.
Veronica
V
Soloveva
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Andrew D
AD
Haddow
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Farooq
F
Nasar
US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702, USA.
Sina
S
Bavari
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Michael C
MC
Bassik
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Stanley N
SN
Cohen
Keck Graduate Institute, Claremont, CA 91711, USA.
Anastasia
A
Levitin
Keck Graduate Institute, Claremont, CA 91711, USA.
Mikhail
M
Martchenko
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