Clinical Microbiology Newsletter
Clostridium botulinum neurotoxins — applications in medicine and potential agents of bioterrorism

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Abstract

Botulism is one of the distinctive diseases known to humankind. Botulism is characterized by a flaccid paralysis progressing to suffocation and death in severe cases that do not receive adequate treatment. Botulism is caused by clostridial neurotoxins with extraordinary potency and neurospecificity. The disease is a true toxemia, in which the neurotoxins are the responsible agents, and the bacteria are not directly involved in paralytic symptoms. Botulinum neurotoxin (BoNT) is produced by strains of neurotoxigenic clostridia, including Clostridium botulinum, as well as rare strains of Clostridium baratii and Clostridium butyricum.

During the past two decades, because of new knowledge about the cellular biology and pharmacology of BoNT, this toxin has become an important tool in cell biology and for the understanding of disease and has stimulated much interest in its actions on the human nervous system. Interest in BoNT has also been raised by awareness of its possible use in bioterrorism, yet the most remarkable discovery that has resulted from investigation of BoNT is its use as a pharmaceutical for the treatment of a myriad of neuronal and hyperactive muscle disorders.

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

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