title: Bacterial persistence by RNA endonucleases.
abstract: Bacteria form persisters, individual cells that are highly tolerant to different types of antibiotics. Persister cells are genetically identical to nontolerant kin but have entered a dormant state in which they are recalcitrant to the killing activity of the antibiotics. The molecular mechanisms underlying bacterial persistence are unknown. Here, we show that the ubiquitous Lon (Long Form Filament) protease and mRNA endonucleases (mRNases) encoded by toxin-antitoxin (TA) loci are required for persistence in Escherichia coli. Successive deletion of the 10 mRNase-encoding TA loci of E. coli progressively reduced the level of persisters, showing that persistence is a phenotype common to TA loci. In all cases tested, the antitoxins, which control the activities of the mRNases, are Lon substrates. Consistently, cells lacking lon generated a highly reduced level of persisters. Moreover, Lon overproduction dramatically increased the levels of persisters in wild-type cells but not in cells lacking the 10 mRNases. These results support a simple model according to which mRNases encoded by TA loci are activated in a small fraction of growing cells by Lon-mediated degradation of the antitoxins. Activation of the mRNases, in turn, inhibits global cellular translation, and thereby induces dormancy and persistence. Many pathogenic bacteria known to enter dormant states have a plethora of TA genes. Therefore, in the future, the discoveries described here may lead to a mechanistic understanding of the persistence phenomenon in pathogenic bacteria.
authors.affiliation: Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4AX, United Kingdom.
authors.forename: Etienne
authors.initials: E
authors.lastname: Maisonneuve
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Shakespeare
authors.forename: Mikkel Girke
authors.initials: MG
authors.lastname: Jørgensen
authors.forename: Kenn
authors.initials: K
authors.lastname: Gerdes
mesh_terms: D000992:Antitoxins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D048168:Escherichia coli K12 / Q000166:cytology / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000378:metabolism; D049070:Protease La / Q000378:metabolism; D012329:RNA, Bacterial / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000992:Antitoxins; D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D012329:RNA, Bacterial; D012333:RNA, Messenger; C465566:RelE protein, E coli; D004722:Endoribonucleases; D049070:Protease La