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Remarkable functional convergence: Type I and II toxin‐antitoxins induce multidrug tolerance by (p)ppGpp‐dependent mechanisms
Author(s) -
Gerdes Ken
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.404.2
Subject(s) - antitoxin , multidrug tolerance , biology , antisense rna , microbiology and biotechnology , cell , effector , escherichia coli , regulator , population , toxin , chemistry , gene , gene expression , biochemistry , biofilm , genetics , bacteria , demography , sociology
Using single‐cell technology, we showed previously that, in Escherichia coli , the ubiquitous bacterial stress alarmone (p)ppGpp (Magic Spot) is a central regulator of both spontaneous and environmentally induced persistence1. The (p)ppGpp level varied stochastically in a population of exponentially growing cells and the high (p)ppGpp level in the rare cells induced persistence. Persister cell formation depended on 10 type II toxin – antitoxin (TA) modules encoding RNases that reversibly inhibit translation by cleavage of mRNA or rRNA2. More recently, another research group showed that a type I TA module ( hokB / sokB ) of E. coli can induce persistence by a mechanism that also depends on (p)ppGpp and, and surprisingly, the highly conserved GTPase Obg3. Type I TAs encode small proteins that depolarize the cell membrane and confer membrane damage and rapid cell killing when overexpressed. By contrast, moderate expression of Hok toxins depletes the ATP pool and induce drug tolerance4. Expression of these highly toxic proteins is repressed by cis ‐acting antisense RNAs5. A complex folding pathway allows the mRNA to escaping irreversible inactivation by the antisense and expression of the toxin in the absence of transcription6,7. However, it is not yet known how (p)ppGpp and Obg induce HokB expression and how the cell recover from Hok‐induced ATP‐depletion and stasis. Nevertheless, these results together reveal Magic Spot as the central regulator and toxin ‐ antitoxins as the central effectors of persister cell formation in E. coli . Support or Funding Information This work was supported by the Danish National Research Foundation (grant identifier DNRF120), a Novo Nordisk Foundation Laureate Research Grant and the ERC Advanced Investigator Grant PERSIST (294517).