Basic Chemistry of Botulinum Neurotoxins Relevant to Vaccines, Diagnostics, and Countermeasures

Abstract

Botulinum neurotoxins (BoNTs) produced by the Clostridium family of bacteria are the deadliest of all naturally occurring toxins and are listed as the highest risk biothreat agents by the Centers for Disease Control and Prevention (CDC). They are the causative agents of botulism, a severe neuroparalytic disease which can be fatal in the absence of medical care. While natural cases of botulism are rare, by virtue of their extreme toxicity, easy production, and dissemination, BoNTs could potentially be employed as biowarfare agents and hence pose great threat to national security and public health. Nevertheless, the ability of these toxins to disrupt neurotransmission has been put to good use, and this potentially lethal toxin is now being used therapeutically in an ever expanding list of medical disorders and cosmetic treatments. A combination of features including neuronal target sites, efficient cellular entry, and unique enzymatic activity contributes to the extreme toxicity of BoNTs. Botulinum neurotoxins have a multi-domain structure with each domain contributing to a specific role in the toxin action. Recent advancements in deciphering the molecular mechanism of action of BoNTs and their structure-function relationship have facilitated a greater understanding of the potential use of individual domains of the toxin in the development of potent antidotes against botulism. Numerous biodefense efforts have been directed toward the development of improved technologies for botulism detection/diagnosis and for developing effective countermeasures, including vaccines, peptides, and small-molecule inhibitors.