Bacterial exotoxins are scary things. The names of the big three: Tetanus, Anthrax and Botulinum, are sufficient to evoke fear and conjure up images of agony, paralysis, mass hysteria, and permanently frozen Hollywood faces. The worst toxin stories are hard to forget. I can still remember the gruesome textbook case studies that accompanied my bacteriology college lectures. There were the home-canning-gone-horribly-awry botulism stories, the historical examples of agonizing tetanus poisonings, and the less lethal but still nasty cases of fast-acting staph toxins delivered to unsuspecting airline passengers in re-heated meals (avoid the ham sandwiches!). It’s all coming flooding back to me.
So, a healthy respect for bacterial toxins is not a bad thing. The worst ones are highly potent and lethal, others may be less potent but are still capable of delivering effects from temporary misery to long-lasting debilitation. But it’s not all bad news. As any microbiology student knows, studies of bacterial toxins have led to some of the most significant advances in the history of medicine–the most well-known example being the development of vaccines based on denatured, inactive forms of toxins. Tetanus and diphtheria are the classic examples where knowledge of the properties of the toxin itself proved to be the key to developing treatment strategies.
In more recent years researchers have been able to effectively apply their understanding of bacterial toxins to design drugs that can selectively target and kill tumor cells. Immunotoxin-based drugs are hybrid molecules composed of a targeting element such as an antibody or ligand, which binds to a receptor on the surface of tumor cells, and a toxin component that enters and kills the cell. Virulent strains of Pseudomonas aeruginosa, a common cause of hospital acquired infections in vulnerable individuals, secrete Exotoxin A—a protein toxin that kills cells by inhibiting protein synthesis. A truncated fragment of Exotoxin A has been used as a component of several immunotoxin therapy drug candidates. One example is BL22, a treatment for CD22-positive lymphomas, which uses a monoclonal antibody to bind to the CD22 cell-surface antigen, and a truncated Exotoxin A fragment to kill the cells.
A paper published in the Clinical Cancer Research in July described a new agent for the treatment of HER2-expressing breast cancers that is a variation on this theme. The paper describes Affitoxin, an agent that combines an Exotoxin A fragment and a small HER2-targeting molecule called an affibody. Affitoxin was first described in a J. Immunotherapy paper published in 2009, and the July paper reported promising positive results using Affitoxin to target HER2-positive tumors in a mouse model.
Two other papers published earlier this year further illustrate how continuing research into the mechanism of action of bacterial toxins is generating new ideas on future treatment options for bacterial infections. For example, certain bacteria that produce toxins are protected from the effect of their own toxin because they synthesize an inhibitor or antitoxin. A paper on toxin:antitoxin regulation in Strep pyogenes, published in the February issue of Structure, illustrates how it may be possible to design new antibiotics that inactivate innate antitoxins and eliminate virulent, toxin-producing strains by leaving them vulnerable to the effects of their own toxin.
Pseudomonas Exotoxin A and the potent plant toxin Ricin both follow similar pathways within human cells. The authors of a paper published earlier this year in Developmental Cell conducted a genome-wide study to identify the genes which Ricin and Exotoxin A interact with in order to kill the cell. They used RNAi screens to identify the genes required for intoxication and to investigate the similarities and differences between both systems. They found only 13% overlap, but identified one gene that is required for both Ricin and Exotoxin A intoxication that may be another attractive target for therapeutics. An agent that blocked ERGIC2 function would potentially be an antidote to both toxins.
We have known about bacterial toxins for many years, and toxoid vaccines were developed a long time ago. These recent papers show how continued research into how bacterial toxins interact with both host and bacterial cells continues to yield important information that is highly relevant to human health and disease.
Zielinski R, Lyakhov I, Hassan M, Kuban M, Shafer-Weaver K, Gandjbakhche A, & Capala J (2011). HER2-affitoxin: a potent therapeutic agent for the treatment of HER2-overexpressing tumor
s. Clinical cancer research : an official journal of the American Association for Cancer Research, 17 (15), 5071-81 PMID: 21791637
Moreau D, Kumar P, Wang SC, Chaumet A, Chew SY, Chevalley H, & Bard F (2011). Genome-wide RNAi screens identify genes required for Ricin and PE intoxications. Developmental cell, 21 (2), 231-44 PMID: 21782526
Smith, C., Ghosh, J., Elam, J., Pinkner, J., Hultgren, S., Caparon, M., & Ellenberger, T. (2011). Structural Basis of Streptococcus pyogenes Immunity to Its NAD+ Glycohydrolase Toxin Structure, 19 (2), 192-202 DOI: 10.1016/j.str.2010.12.013