The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

Abstract

A large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide‐bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase–thioredoxin (TrxR‐Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR‐Trx also prevent botulism. On this basis, we propose that ebselen and PX‐12, two TrxR‐Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism.

Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin

“…Following the demonstration that the cytosolic reduction of the interchain disulphide bond of CNTs is essential to enable their metalloprotease activity [23,24] and the recent finding that TrxR-Trx inhibitors prevent the toxicity of all BoNT serotypes [45], we investigated whether TrxR-Trx inhibitors prevent TeNT intoxication in vitro.…”

“…After membrane translocation, the interchain disulphide bond of BoNTs and TeNT is reduced by the NADPH-Thioredoxin Reductase-Thioredoxin (TrxR-Trx) system, [17][18][19][20][21][22]. This step leads to the release of the L chain from the SV surface into the cytosol [23,24], thus enabling their catalytic activity [24,25]. Within the cytosol, the L metalloproteases selectively cleaves specific members of the SNARE protein family [3,5,25,26], which are essential constituents of the SV neurotransmitter release machinery [27].…”

Foodborne Botulism: Clinical Diagnosis and Medical Treatment

“…The bont-producing clostridia generate a polypeptide toxin (150,000 Daltons) that acts specifically on neuromuscular junctions and cholinergic sites within the autonomic nervous system (all ganglionic synapses and post-ganglionic parasympathetic synapses) by binding to receptors located on the presynaptic membrane. After that, by endocytosis and through a complex processes [e.g., translocation of light chain (Lc) into the cytosol and cleavage of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), by the metalloproteinase activity of the Lc] the toxin blocks the normal calcium-associated quantal release of acetylcholine from the presynaptic nerve terminals: this process is irreversible [ 14 ].…”

“…Efforts have been invested on designing small molecules, peptidic inhibitors, aptamers as well as on testing some natural substances for their anti-botulinum activity [ 13 ]. Studies on specific inhibitors effective in preventing the neuroparalytic action of BoNTs (irrespectively of their serotype and subtype) which could be used in poisoned patients without knowing the particular type of BoNT are underway and appear to be promising for the future [ 13 , 14 , 53 , 57 , 58 , 59 ]. Current drug research efforts have mainly focused on BoNT/A and mainly addressed on light chain proteolytic activity.…”

Structural flexibility of the tetanus neurotoxin revealed by crystallographic and solution scattering analyses

“…As a result, the function of inhibitory interneurons is lost, leading to spasms and stiffness in muscles. A horrible outcome of tetanus poisoning is that the patient is fully conscious during such complications and experiences extreme pain ( Rossetto et al, 2019 ). There are no specific drugs to cure tetanus.…”