A Biologically-Based Computational Approach to Drug Repurposing for Anthrax Infection

Abstract

Developing drugs to treat the toxic effects of lethal toxin (LT) and edema toxin (ET) produced by B. anthracis is of global interest. We utilized a computational approach to score 474 drugs/compounds for their ability to reverse the toxic effects of anthrax toxins. For each toxin or drug/compound, we constructed an activity network by using its differentially expressed genes, molecular targets, and protein interactions. Gene expression profiles of drugs were obtained from the Connectivity Map and those of anthrax toxins in human alveolar macrophages were obtained from the Gene Expression Omnibus. Drug rankings were based on the ability of a drug/compound’s mode of action in the form of a signaling network to reverse the effects of anthrax toxins; literature reports were used to verify the top 10 and bottom 10 drugs/compounds identified. Simvastatin and bepridil with reported in vitro potency for protecting cells from LT and ET toxicities were computationally ranked fourth and eighth. The other top 10 drugs were fenofibrate, dihydroergotamine, cotinine, amantadine, mephenytoin, sotalol, ifosfamide, and mefloquine; literature mining revealed their potential protective effects from LT and ET toxicities. These drugs are worthy of investigation for their therapeutic benefits and might be used in combination with antibiotics for treating B. anthracis infection.

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

“…This hypothesis was strengthened by the anti‐DT effects of these compounds. In addition, both of these compounds were described previously as antitoxin drugs—amodiaquine inhibits cathepsin B, a lysosomal protease implicated in vesicle acidification—and has broad spectrum applications, while bepridil was previously shown to protect cells from anthrax toxin, as well as DT …”

“…In addition, both of these compounds wered escribed previously as antitoxin drugs-amodiaquine inhibits cathepsin B, al ysosomal protease implicated in vesiclea cidification-and has broad spectrum applications, [38,43] while bepridilw as previously shown to protect cells from anthraxt oxin,asw ell as DT. [44,45] Monensin and the structurally relatedl asalocid are cationic ionophores used as veterinary antiparasitic drugs. In all performed assays, monensin and lasalocid strongly protected HUVECs and HeLa cells at low concentrationsf rom both CNF1 and DT challenges.…”

Μοντελοποιήση Κυτταρικής Απόκρισης Με Μεθόδους Βελτιστοποιήσης

“…This chapter presents the work published in [101]. The chapter follows the original work closely, with slight changes to ensure a uniform style for this thesis.…”