title: Cross-inhibition of pathogenic agents and the host proteins they exploit.
abstract: The major limitations of pathogen-directed therapies are the emergence of drug-resistance and their narrow spectrum of coverage. A recently applied approach directs therapies against host proteins exploited by pathogens in order to circumvent these limitations. However, host-oriented drugs leave the pathogens unaffected and may result in continued pathogen dissemination. In this study we aimed to discover drugs that could simultaneously cross-inhibit pathogenic agents, as well as the host proteins that mediate their lethality. We observed that many pathogenic and host-assisting proteins belong to the same functional class. In doing so we targeted a protease component of anthrax toxin as well as host proteases exploited by this toxin. We identified two approved drugs, ascorbic acid 6-palmitate and salmon sperm protamine, that effectively inhibited anthrax cytotoxic protease and demonstrated that they also block proteolytic activities of host furin, cathepsin B, and caspases that mediate toxin's lethality in cells. We demonstrated that these drugs are broad-spectrum and reduce cellular sensitivity to other bacterial toxins that require the same host proteases. This approach should be generally applicable to the discovery of simultaneous pathogen and host-targeting inhibitors of many additional pathogenic agents.
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Leeor
authors.initials: L
authors.lastname: Zilbermintz
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: William
authors.initials: W
authors.lastname: Leonardi
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Tran
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Josue
authors.initials: J
authors.lastname: Zozaya
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Mathew-Joseph
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Liem
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Levitin
authors.affiliation: Keck Graduate Institute, Claremont, CA 91711, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Martchenko
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D001408:Bacillus anthracis; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D055808:Drug Discovery; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D008297:Male; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D011479:Protamines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D012474:Salmon / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011479:Protamines; D011480:Protease Inhibitors; C030325:anthrax toxin; D010447:Peptide Hydrolases; D045683:Furin; D002401:Cathepsin B; D001205:Ascorbic Acid