The Microbiology and Botulism Research Unit (MBRU) puts a major focus on the development of therapies for treating botulism, a disease caused by a family of highly potent neurotoxins produced by Clostridia botulinum (for more information, see the CDC botulism website). Botulism is usually contracted through the consumption of contaminated food, particularly canned foods. Because of their toxicity and ease of production, the botulinum family of neurotoxins is classified as a Category A bioterrorism threat. The toxins cause flaccid paralysis by entering peripheral neurons and cleaving specific synaptosomal proteins involved in exocytosis, thus blocking neurotransmitter release. Seven different botulinum neurotoxin serotypes (A-G) are known in nature, many serotypes having a number of isotypic variants. These toxins are the most potent known to man and consist of a 100 kDa heavy chain (HC) and a 50 kDa light chain (LC). The HC contains the translocation and receptor binding domains while the LC contains the catalytic protease domain.

Since the Botulism Therapeutics Program began in 2004, we have established an approved BL2 select agent laboratory and core technologies such as an in vitro cell bioassay laboratory and an in vivo mouse bioassay laboratory. Many different projects have been supported within this program which are now completed; including botulism antitoxin development, characterizing proteomic modulations that occur following neuron intoxication, neuronal proteins that interact with botulinum proteases, and enzymatic modifications to the toxin protease within neurons. Four major research projects remain underway.

Overview of Program:

Botulism Therapeutics Projects:

Tufts in vivo toxin testing core (Project leader, Dr. Jean Mukherjee)
This project, entitled "Establishment of a Botulism Therapeutics Testing Facility", involves the construction and commissioning of a testing facility at Tufts that is capable of testing the efficacy of therapeutic agents to treat botulism post-exposure or to reverse existing intoxication.

Tufts in vitro bioassay core (Project leader, Dr. Jong-Beak Park)
This project entitled "Development of In Vitro Assays to Evaluate the Anti-BoNT Effects of Potential Therapeutic Agents" involves the development and performance of a core facility that performs botulism bioassays in neuronal cell culture systems.

New small molecule anti-toxin drugs (Project leader, Dr. Charles Shoemaker)
Two separate botulism drug discovery projects are underway.

1. One project, entitled "Integrated Team Approach to the Development of Botulism Drugs" is in collaboration with Absolute Science (Dr. Alan Jacobson) for medicinal chemistry and the Laboratory of Dr. Allen at Boston University for structural studies. This project is using rational drug design to develop BoNT drugs with a focus on BoNT/A.

2. 1.A second project, entitled " Development of Small Molecule Inhibitors for Botulinum Neurotoxin Type B", is in collaboration with the Laboratory of Dr. Kim Janda at Scripps Institute. This project is primarily employing computer-aided rational drug design to develop BoNT drugs with a focus on BoNT/B.

Agents that target toxins for proteasome degradation (Project leader, Dr. Charles Shoemaker)
Through a project entitled "Agents that therapeutically reduce botulism persistence" we are developing designer E3 ligases that bind to BoNT protease and direct its ubiquitination and its subsequent accelerated proteasomal destruction. We are also collaborating with USAMRIID to develop atoxic holotoxin delivery systems that will facilitate the uptake of biomolecules to intoxicated neurons and their delivery to the cytosol.