A Natural Product Exhibits Potent Anti-Botulism Efficacy by Accelerating Degradation of Intracellular Toxins

Abstract

Background: Botulinum neurotoxins (BoNTs) are among the deadliest toxins known to humans. To date, there are no approved drugs to treat botulism after intoxication of the motor neuron. Intensive efforts have been made to develop small-molecule inhibitors, however, few possess noteworthy in vivo efficacy. Methods: The primary rat cerebellar granule neuron (CGN)-based screening was performed to discover novel effective inhibitors against BoNT/A in neural cells. The anti-botulism mechanism of embelin was preliminary studied in the impact of embelin on the main steps of BoNTs intoxication and intracellular duration. The anti-botulism efficacy of natural product embelin on botulinum toxin type A and type B was assessed in BALB/c mouse. Findings: We discovered a promising anti-BoNTs natural poduct embelin, which could protect 80% and 60% of the mice against lethal dose of BoNT/A or BoNT/B at 1 h after toxin exposure, respectively. Moreover, at 8 h after toxin exposure, embelin still protect 30% and 35% of the mice against lethal dose of BoNT/A or BoNT/B. In addition, mechanism analysis proved that embelin could significantly speed up the clearance of BoNTs in neurons. Interpretation: We discovered a promising anti-BoNTs natural product embelin, which could protect mice against lethal dose of BoNTs. The novel botulism antidote will be useful for reducing the morbidity of BoNTs intoxication and have potential biodefense implications. Funding Statement: We acknowledge this work was supported by National Key R&D Program of China (2017YFC1200905), National Key Basic Research Program (973) of China (2015CB554202), and the Beijing Nova Program (Z181100006218111) for funding. Declaration of Interests: The authors declare no competing financial interest. Ethics Approval Statement: The Beijing Institute of Microbiology and Epidemiology Animal Care and Use Committee approved our study protocol. The animal care and use protocol adhered to the regulations of the Institutional Animal Care and Use Committee (IACUC).