RETRACTED: 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.

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

“…Ectopic overexpression of ribonucleases (RelE and MazF toxin), HipA (a glutamyl transfer RNA synthetase protein kinase) and TisB (membrane damage protein) enhances drug tolerance in bacteria 39,[62][63][64] . In E. coli, TA systems function synergistically, and the successive deletion of 10 TA systems progressively reduces persister cell formation in vitro 8 . In this study, we observed that MazEF TA systems are differentially induced in Mtb persisters, and simultaneous deletion of MazF3, MazF6 and MazF9 significantly reduced persister cell formation in vitro.…”

“…TA systems are widespread in bacterial genomes and contribute to prokaryotic stress adaptation and the formation of persister cells and biofilms 1,[7][8][9] . The toxin components of the TA modules exert their effects in different ways by targeting essential cellular functions such as DNA replication, protein synthesis, cell division, peptidoglycan biosynthesis and ribosome assembly; however, RNA cleavage is the most prevalent mode of action [10][11][12][13][14][15][16] .…”

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

“…7,12,31,32 Although TAs are key players in adjusting physiology during adaptation processes, how bacteria coordinate their expression individually and as a whole set remain poorly understood. 15,[33][34][35][36][37] In particular, a limited number of studies have focused on putative crosstalks between TAs. For instance in E. coli, the TA-II endoribonuclease toxin MsqR was shown to enhance a selective degradation of the ghoST mRNA in favor of the type V TA toxin GhoT, by direct cleavage within the ghoS sequence and, a complex regulatory interplay has been unveiled between several TA-II modules.…”

Hypothesis: type I toxin–antitoxin genes enter the persistence field—a feedback mechanism explaining membrane homoeostasis

“…Numbers on the x-axis refer to the number of TA loci that were deleted in the strains tested. Adapted from Maisonneuve et al [35].…”