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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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Features of type II TAs. Typical type II TAs consists of two genes organized as an operon. The antitoxin gene precedes the toxin one. Both genes usually overlap and are co-transcribed from one or two promoters. TA genes encode both antitoxin (oval) and toxin (crescent) proteins that bind to each other and generate a harmless complex under normal conditions. The antitoxin protein also binds to its own promoter to negatively autoregulate the TA operon. The toxin protein is not able to bind to the promoter by itself, but serves as a co-repressor upon binding of the antitoxin to the promoter, to further repress transcription of the operon. Under stressful circumstances, the antitoxin protein which is more labile, is degraded more rapidly by the host proteases and thus liberate the toxin protein to act on the cell target.
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fig1: Features of type II TAs. Typical type II TAs consists of two genes organized as an operon. The antitoxin gene precedes the toxin one. Both genes usually overlap and are co-transcribed from one or two promoters. TA genes encode both antitoxin (oval) and toxin (crescent) proteins that bind to each other and generate a harmless complex under normal conditions. The antitoxin protein also binds to its own promoter to negatively autoregulate the TA operon. The toxin protein is not able to bind to the promoter by itself, but serves as a co-repressor upon binding of the antitoxin to the promoter, to further repress transcription of the operon. Under stressful circumstances, the antitoxin protein which is more labile, is degraded more rapidly by the host proteases and thus liberate the toxin protein to act on the cell target.

Mentions: We will analyse the potential use of type II TAs as antimicrobial targets since they are the most abundant and better studied among TAs, and their mechanisms of action have been generally unveiled. Type II TAs exhibit typical features (Fig. 1) such as (i) the antitoxin gene is usually preceding the toxin gene; (ii) both genes are co-transcribed from a promoter located upstream of the antitoxin gene and (iii) they are translationally coupled. The operon is negatively autoregulated by the antitoxin upon binding to an operator region that overlaps the single promoter of the operon, whereas the toxin acts as an efficient co-repressor. The antitoxin protein is labile and more susceptible to degradation by the host proteases, while the toxin protein is much more stable. The ratio of the toxin to antitoxin is important to determine the stoichiometry of the TA protein complex and also to regulate the transcription of the operon, so that the antitoxin is replenished to shield the toxicity in normal condition (Monti et al., 2007; Cataudella et al., 2012). However, under certain stressful circumstances such as nutritional stress, colonization of new hosts, DNA-damaging agents, etc., transcription of the TA will be triggered, and the labile antitoxin will be degraded more rapidly, unleashing the toxin protein to act on their targets.


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

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

Features of type II TAs. Typical type II TAs consists of two genes organized as an operon. The antitoxin gene precedes the toxin one. Both genes usually overlap and are co-transcribed from one or two promoters. TA genes encode both antitoxin (oval) and toxin (crescent) proteins that bind to each other and generate a harmless complex under normal conditions. The antitoxin protein also binds to its own promoter to negatively autoregulate the TA operon. The toxin protein is not able to bind to the promoter by itself, but serves as a co-repressor upon binding of the antitoxin to the promoter, to further repress transcription of the operon. Under stressful circumstances, the antitoxin protein which is more labile, is degraded more rapidly by the host proteases and thus liberate the toxin protein to act on the cell target.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig1: Features of type II TAs. Typical type II TAs consists of two genes organized as an operon. The antitoxin gene precedes the toxin one. Both genes usually overlap and are co-transcribed from one or two promoters. TA genes encode both antitoxin (oval) and toxin (crescent) proteins that bind to each other and generate a harmless complex under normal conditions. The antitoxin protein also binds to its own promoter to negatively autoregulate the TA operon. The toxin protein is not able to bind to the promoter by itself, but serves as a co-repressor upon binding of the antitoxin to the promoter, to further repress transcription of the operon. Under stressful circumstances, the antitoxin protein which is more labile, is degraded more rapidly by the host proteases and thus liberate the toxin protein to act on the cell target.
Mentions: We will analyse the potential use of type II TAs as antimicrobial targets since they are the most abundant and better studied among TAs, and their mechanisms of action have been generally unveiled. Type II TAs exhibit typical features (Fig. 1) such as (i) the antitoxin gene is usually preceding the toxin gene; (ii) both genes are co-transcribed from a promoter located upstream of the antitoxin gene and (iii) they are translationally coupled. The operon is negatively autoregulated by the antitoxin upon binding to an operator region that overlaps the single promoter of the operon, whereas the toxin acts as an efficient co-repressor. The antitoxin protein is labile and more susceptible to degradation by the host proteases, while the toxin protein is much more stable. The ratio of the toxin to antitoxin is important to determine the stoichiometry of the TA protein complex and also to regulate the transcription of the operon, so that the antitoxin is replenished to shield the toxicity in normal condition (Monti et al., 2007; Cataudella et al., 2012). However, under certain stressful circumstances such as nutritional stress, colonization of new hosts, DNA-damaging agents, etc., transcription of the TA will be triggered, and the labile antitoxin will be degraded more rapidly, unleashing the toxin protein to act on their targets.

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