Newly Characterized Toxin-Antitoxin Module May Lead to Improved Antibiotics

An international team of molecular microbiologists has detailed the molecular pathway responsible for a toxin-antitoxin system in Escherichia coli that becomes activated when the bacteria are put under stress.

A toxin-antitoxin system is a set of two or more closely linked genes that together encode both a protein “poison” and a corresponding “antidote.” When these systems are contained on plasmids, they ensure that only the daughter cells that inherit the plasmid survive after cell division. If the plasmid is absent in a daughter cell, the unstable antitoxin is degraded and the stable toxic protein kills the new cell.

MazEF, a toxin-antitoxin locus found in E. coli and other bacteria, induces programmed cell death in response to starvation, specifically a lack of amino acids. This releases the cell's contents for absorption by neighboring cells, potentially preventing the death of close relatives, and thereby increasing the inclusive fitness of the cell that perished. The toxin portion MazF is an endoribonuclease that cleaves single-stranded mRNAs at ACA (adenine-cytosine-adenine) sequences.

Investigators at the Hebrew University of Jerusalem (Israel) and the University of Vienna (Austria) reported in the September 30, 2011, issue of the journal Cell that MazF cleaved RNA molecules at ACA sites at or closely upstream of the AUG (adenine-uracil- guanine) start codon of some specific mRNAs and thereby generated leaderless mRNAs. Moreover, MazF also targeted 16S rRNA within 30S ribosomal subunits at the decoding center, thereby removing 43 nucleotides from the 3-prime terminus. As this region comprises the anti-Shine-Dalgarno (aSD) sequence that is required for translation initiation on canonical mRNAs, a subpopulation of ribosomes is formed that selectively translates the described leaderless mRNAs both in vivo and in vitro.

The characterization of this particular toxin-antitoxin module may lead to new approaches to the design of improved, novel antibiotics that would effectively utilize the stress-inducing mechanism process in order to destroy more efficiently pathogenic bacteria.

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Hebrew University of Jerusalem
University of Vienna