Toxins, modes of action

Corbel S, Mougin C, Bouaicha N. Cyanobacterial toxins modes of action, fate in aquatic and soil ecosystems, phytotoxicity and bioaccumulation in agricultural crops. 

Collier RJ (1975) Diphtheria toxin Mode of action and structure. Bacteriol Rev 39 54-85... 

Jurat-Fuentes, J.L. and M. Adang. 2006. Cry toxin mode of action in susceptible and resistant Heliothis virescens larvae. J. Invertebr. Pathol. 92 166-171. 

Type of intoxication Genera responsible Main toxins Mode of action... 

Bacillus thuringiensis produces a variety of organic compounds which are toxic to the larvae of certain susceptible insect hosts. Among the toxic entities are proteinaceous crystals, probably three soluble toxins, and certain enzymes. The protein material is the major toxin active in killing lepidopterous larvae. The protein is formed by the cells apparently in close synchrony with sporulation, and its nature is a constant function of bacterial strain. The mode of action of the protein is under study. The sequence of events in the pathology observed is probably solubilization of the crystal (enzymatic or physical)—>liberation of toxic unit—>alteration of permeability of larval gut wall— change in hemolymph pH—>invasion of hemolymph by spores or vegetative cells of the bacterium. 

Further work on the spectrum of toxicity of these toxins, as well as their mode of action in disease development, is under way. 

Gill, D.M., Pappenheimer Jr, A.M, Brown, R., and Kurnick, J.T. (1969) Studies on the mode of action of diphtheria toxin VII. Toxin-stimulated hydrolysis of nicotinimide adenine dinucleotide in mammalian cell extracts./. Exp. Med. 129, 1-21. 

Generally, there are three major types of bacterial exotoxins that differ with respect to their structure and principle mode of action. First, there are toxins that attack the cell membrane and thereby damage eukaryotic... 

Mode of action Activation of macrophages/monocytes release of endogenous mediators such as lipids from arachidonic acid, reduced oxygen species, proteins 1. Pore formation in cell membranes 2. Enzymatic modification of specific substrates in the cytosol of host cells (AB-type toxins) 3. Superantigen stimulation of the immune system... 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Figure 1 The mode of action for bacterial AB-type exotoxins. AB-toxins are enzymes that modify specific substrate molecules in the cytosol of eukaryotic cells. Besides the enzyme domain (A-domain), AB-toxins have a binding/translocation domain (B-domain) that specifically interacts with a cell-surface receptor and facilitates internalization of the toxin into cellular transport vesicles, such as endosomes. In many cases, the B-domain mediates translocation of the A-domain into the cytosol by pore formation in cellular membranes. By following receptor-mediated endocytosis, AB-type toxins exploit normal vesicle traffic pathways into cells. One type of toxin escapes from early acidified endosomes (EE) into the cytosol, thus they are referred to as short-trip-toxins . In contrast, the long-trip-toxins take a retrograde route from early endosomes (EE) through late endosomes (LE), trans-Golgi network (TGN), and Golgi apparatus into the endoplasmic reticulum (ER) from where the A-domains translocate into the cytosol to modify specific substrates.

Figure 2 The actin-ADP-ribosylating toxins, (a) Molecular mode of action. The actin-ADP-ribosylating toxins covalently transfer an ADP-ribose moiety from NAD+ onto Arg177 of G-actin in the cytosol of targeted cells. Mono-ADP-ribosylated G-actin acts as a capping protein and inhibits the assembly of nonmodified actin into filaments. Thus, actin polymerization is blocked at the fast-growing ends of actin filaments (plus or barbed ends) but not at the slow growing ends (minus or pointed ends). This effect ultimately increases the critical concentration necessary for actin polymerization and tends to depolymerize F-actin. Finally, all actin within an intoxicated cell becomes trapped as ADP-ribosylated G-actin.

The binary nature of iota toxin from C. perfringens type E was first explored in 1986 by Stiles and Wilkins. The overall mode of action for iota toxin is widely comparable to C2 toxin. The binding/translocation component iota b (Ib) facilitates cellular uptake of the enzyme component iota a (la) in a like manner as previously described for C2 toxin. la, just as C2I, specifically mono-ADP-ribosylates G-actin at Argl77. ... 

To remain a step ahead of life-threatening pathogens, it is essential to understand the chemical nature, structure, and diverse modes of action for bacterial toxins which represent some of the most toxic substances known today. Based upon this information, new vaccines can be created against specific domains of a toxin or perhaps cellular uptake of the toxins can be blocked by specific pharmacological inhibitors. Therefore, it will be of lasting impact to transfer our increasing knowledge of bacterial toxins from the laboratory bench into the clinic. 

His major scientific interests are bacterial virulence and various aspects of bacteriocins and toxins including quorum sensing regulation, mode of action, and mechanisms involved in immunity and receptor targeting. 

Baden, D. and Trainer, V.L., Mode of action of toxins of seafood poisoning, in Falconer, I.R., ed., Algal Toxins in Seafood and Drinking Water, Academic Press, San Diego, 1993. 

Sakaguchi, G., Molecular structure of Clostridium botulinum progenitor toxins, in Portland, A.L., Dowel, V.R. and Richard, I.L., eds.. Microbial Toxins in Foods and Feeds. Cellular and Molecular Modes of Action, Plenum Press, New York, pp. 173-180, 1990. 

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