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One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan WT, Balsa D, Espinosa M - FEMS Microbiol. Rev. (2015)

Bottom Line: The result is a cessation of cell growth or even death.Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair.Possible ways of delivery and formulation of Tas are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.

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Proposed strategies to use TA as antimicrobials. A few approaches have been suggested to make use of the toxin (crescent) of the pathogen itself for self-killing: Inhibition of TA transcription (I) or inhibition of antitoxin (oval) translation (II), thus antitoxin cannot be replenished and once the remaining antitoxin is degraded, the toxin will be free to act on the bacterial cell; Activation of host proteases (III) to rapidly degrade the labile antitoxin proteins and disruption of TA protein complex by i-PPI (IV) to liberate the toxin, as well as triggering activation of TA by quorum sensors (V).
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fig5: Proposed strategies to use TA as antimicrobials. A few approaches have been suggested to make use of the toxin (crescent) of the pathogen itself for self-killing: Inhibition of TA transcription (I) or inhibition of antitoxin (oval) translation (II), thus antitoxin cannot be replenished and once the remaining antitoxin is degraded, the toxin will be free to act on the bacterial cell; Activation of host proteases (III) to rapidly degrade the labile antitoxin proteins and disruption of TA protein complex by i-PPI (IV) to liberate the toxin, as well as triggering activation of TA by quorum sensors (V).

Mentions: A number of different strategies have been suggested as possible means to the druggability of toxins (Mutschler and Meinhart 2011; Chan et al., 2013; Gerdes 2013; Unterholzner, Poppenberger and Rozhon 2013). These strategies are based on the finding that the antitoxin is more susceptible to degradation by the host proteases than its cognate toxin. Therefore, by inhibiting the replenishment of the antitoxin, the toxin will be released and can exhibit its toxicity to the cells while its cognate antitoxin is degraded. We can conceive a number of strategies, all having their pros and cons, as schematized in Fig. 5.


One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan WT, Balsa D, Espinosa M - FEMS Microbiol. Rev. (2015)

Proposed strategies to use TA as antimicrobials. A few approaches have been suggested to make use of the toxin (crescent) of the pathogen itself for self-killing: Inhibition of TA transcription (I) or inhibition of antitoxin (oval) translation (II), thus antitoxin cannot be replenished and once the remaining antitoxin is degraded, the toxin will be free to act on the bacterial cell; Activation of host proteases (III) to rapidly degrade the labile antitoxin proteins and disruption of TA protein complex by i-PPI (IV) to liberate the toxin, as well as triggering activation of TA by quorum sensors (V).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487406&req=5

fig5: Proposed strategies to use TA as antimicrobials. A few approaches have been suggested to make use of the toxin (crescent) of the pathogen itself for self-killing: Inhibition of TA transcription (I) or inhibition of antitoxin (oval) translation (II), thus antitoxin cannot be replenished and once the remaining antitoxin is degraded, the toxin will be free to act on the bacterial cell; Activation of host proteases (III) to rapidly degrade the labile antitoxin proteins and disruption of TA protein complex by i-PPI (IV) to liberate the toxin, as well as triggering activation of TA by quorum sensors (V).
Mentions: A number of different strategies have been suggested as possible means to the druggability of toxins (Mutschler and Meinhart 2011; Chan et al., 2013; Gerdes 2013; Unterholzner, Poppenberger and Rozhon 2013). These strategies are based on the finding that the antitoxin is more susceptible to degradation by the host proteases than its cognate toxin. Therefore, by inhibiting the replenishment of the antitoxin, the toxin will be released and can exhibit its toxicity to the cells while its cognate antitoxin is degraded. We can conceive a number of strategies, all having their pros and cons, as schematized in Fig. 5.

Bottom Line: The result is a cessation of cell growth or even death.Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair.Possible ways of delivery and formulation of Tas are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.

Show MeSH