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Obstructing toxin pathways by targeted pore blockage.

The focus of this review is on the biophysical studies of the channel-forming bacterial toxins that shed light upon the mechanisms of their toxicity and propose new approaches to block their virulent action. Extensive data on the structural features of these toxins, the mechanisms of their secretion, proteolytic activation, extracellular receptors, enzymatic intracellular action, and cellular responses will be mostly omitted here. We refer our reader to several excellent specialized books and reviews that cover this material in the finest detail1–15. 
 
1.1. Channel-blocking and channel-forming toxins 
In the course of evolution, Nature created numerous toxins, which selectively target ion channels of excitable cells16–18. Regardless of which version of Cleopatra's self-poisoning is true, the toxin-triggered modification of channel function was certainly involved. She either suffered from intoxication following blockage of her ligand-gated channels by the Egyptian cobra venom or from poisonous action of the chloride channel inhibitor extracted from cicuta. Numerous studies of the neurotoxins' biological functions allowed not only for deeper understanding of the structural and functional features of several channels of excitable membranes, but also for developing the pharmaceutical approaches to use these toxins for therapeutic purposes. Conversely, among the great variety of virulence factors secreted by different organisms, there is a significant group of toxins (mostly bacterial) that, instead of blocking channels, are able to form ion-conductive pores in membranes of the targeted cells. For most of them, there are no antidotes or antitoxins developed and approved for human use. At the same time, one of the possible ideas to target the bacterial exotoxins is quite simple. Following Nature, which created the channel-inhibiting toxins, it should be possible to design the potent antitoxins specifically blocking the conductive pathways of the channel-forming toxins with an ultimate goal to defend from the cytotoxic action of these agents. This idea is neither preposterous nor new. Indeed, amantadine, the small-molecule blocker of the tetrameric proton-selective M2 channel from the viral envelope of influenza A virus19–21 had been approved for human use back in 1965. Interestingly, even though amantadine is no longer recommended by the CDC for use to treat seasonable influenza due to developed antidrug resistance, the exact mechanism of the amantadine interaction with the M2 channel is still a matter of debates22–29. Even so, the M2 channel is the main target for virtual screening for powerful channel blockers30–34. Therefore, the idea to design and develop the effective blockers of the channels formed by bacterial toxins in target membranes enjoys a well-appreciated attention. Not being able to use the evolutionary path, we can employ the modern single-molecule biophysical approaches to study the pore-forming toxins and their potential inhibitors.