Clinical Microbiology NewsletterClostridium botulinum neurotoxins — applications in medicine and potential agents of bioterrorism
Section snippets
Botulism
The hallmark of botulism is a bilateral descending weakness and paralysis with an extremely long duration of paralysis of months to years in severe cases. Botulism in humans can weaken or paralyze every skeletal muscle in the body. BoNT inhibits acetylcholine exocytosis at parasympathetic and sympathetic neuromuscular synapses. Patients with signs of botulism must be monitored for respiratory difficulties. Although the sensory system and central nervous system (CNS) mentation are generally
Neurotoxigenic clostridia
One of the most interesting features of clostridial organisms is their formation of a wide diversity of toxins. The clostridia produce more types of protein toxins than any other group of microorganisms; more than 20 protein toxins have been identified from clostridia, some with very high potencies in animals and humans. At least 15 species of Clostridium are known to produce protein toxins. These agents include neurotoxins, lipases, lecithinases, hemolysins, enterotoxins, cytotoxins,
Botulinum neurotoxin structure and function
BoNTs comprise a related family of neurotoxins that are produced as single-chain protein molecules of ca. 150 kDa. They achieve their characteristic high toxicities of 107 to 108 mouse 50% lethal dose per mg by posttranslational proteolytic cleavage to form a di-chain molecule composed of a light (L) chain (∼50 kDa) and a heavy (H) chain (∼100 kDa) linked by a disulfide bond. Depending on the serotype, BoNT occurs naturally in large toxin complexes (∼300 kDa to ∼900 kDA), in which the BoNT
Historical development of botulinum toxin as a pharmaceutical
The general principle in the development of botulinum toxin as a therapeutic followed the concept of “graded selective denervation” for alteration of involuntary muscle activity, but with retention of voluntary muscle function. The concept of using botulinum toxin as a selective chemodenervating agent was probably considered for many years by neurologists. However, Drachman's provocative studies at Johns Hopkins University of the effects of botulinum toxin in developing chicken embryos provided
Botulinum toxin as a potential bioterrorism agent
Because botulinum toxin is the most toxic substance known and is extremely poisonous by the oral route (estimated lethal oral dose, 10 to 70 μg for a 70-kg human) and potentially toxic by inhalation, it has been considered a possible bioterrorism agent. Studies of BoNTs as weapons have been performed by several countries, including Japan, Germany, Russia, Iraq, and the United States. Among the earliest known intentional nefarious use of BoNT was by General Shiro Ishii, the head of the Japanese