RNA-based regulation in type I toxin–antitoxin systems and its implication for bacterial persistence

Current Genetics, May 2017

Bacterial dormancy is a valuable survival strategy upon challenging environmental conditions. Dormant cells tolerate the consequences of high stress levels and may re-populate the environment upon return to favorable conditions. Antibiotic-tolerant bacteria—termed persisters—regularly cause relapsing infections, increase the likelihood of antibiotic resistance, and, therefore, earn increasing attention. Their generation often depends on toxins from chromosomal toxin–antitoxin systems. Here, we review recent insights concerning RNA-based control of toxin synthesis, and discuss possible implications for persister generation.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs00294-017-0710-y.pdf

RNA-based regulation in type I toxin–antitoxin systems and its implication for bacterial persistence

RNA‑based regulation in type I toxin-antitoxin systems and its implication for bacterial persistence Bork A. Berghoff 0 1 E. Gerhart H. Wagner 0 0 Department of Cell and Molecular Biology, Uppsala University , 75124 Uppsala , Sweden 1 Institut für Mikrobiologie und Molekularbiologie, Justus-Liebig-Universität , 35392 Giessen , Germany 2 E. Gerhart H. Wagner Bacterial dormancy is a valuable survival strategy upon challenging environmental conditions. Dormant cells tolerate the consequences of high stress levels and may re-populate the environment upon return to favorable conditions. Antibiotic-tolerant bacteria-termed persisters-regularly cause relapsing infections, increase the likelihood of antibiotic resistance, and, therefore, earn increasing attention. Their generation often depends on toxins from chromosomal toxin-antitoxin systems. Here, we review recent insights concerning RNA-based control of toxin synthesis, and discuss possible implications for persister generation. Communicated by M. Kupiec. * Bork A. Berghoff Toxin-antitoxin; Antisense RNA; 5′ UTR structure; Persistence; Depolarization; SOS response - Every organism’s future is unwritten and to a large extent unpredictable. We—as human beings—are aware of this unpleasant fact and try to safeguard ourselves by sanitary and monetary protection. Even though simple organisms like bacteria are not “aware” of the inevitable risks of life, they have inherited genetic programs that have ensured their survival in the past and will do so in the future. Generating phenotypic heterogeneity in a clonal population of bacteria is considered a successful survival strategy, often referred to as bet-hedging (Veening et al. 2008). For example, most bacteria generate subpopulations of nongrowing (i.e., dormant) cells that can withstand unfavorable environmental conditions (Lennon and Jones 2011). According to the “microbial scout” hypothesis, cells leave dormancy stochastically to sample the environment (Buerger et al. 2012; Sturm and Dworkin 2015). If conditions are favorable, these pioneering cells can re-populate the environment. Even the smallest subpopulation that rides out a catastrophe can ensure continuity of the bacterial species as such. In line with this concept, pathogenic bacteria generate multidrug-tolerant phenotypic variants that have been denoted persisters due to their ability to survive antibiotic treatment (Bigger 1944). Persisters regularly cause relapsing infections and are considered a major risk to public health (Lewis 2010). In contrast to resistant cells, persisters are unable to multiply in the presence of antibiotics, but rather reside in a dormant state which renders them tolerant towards the action of most antibiotics. Multiple pathways by which persisters arise have been described, most often ultimately resulting in slowed down growth via corruption of essential cellular processes. For example, persistence can be triggered by ATP depletion (Conlon et al. 2016; Shan et al. 2017), nutrient shifts, and metabolic perturbations (Amato et al. 2013; Amato and Brynildsen 2014; Radzikowski et al. 2016), stochastic induction of (p)ppGpp (Maisonneuve et al. 2013; Germain et al. 2015), or indole-activated stress responses (Vega et al. 2012). Distinct pathways might be either essential or rather negligible for persister formation, depending on the experimental/environmental conditions. For example, it was recently challenged whether (p)ppGpp-activated pathways are the dominant source of persister cells (Chowdhury et al. 2016; Shan et al. 2017), and clearly, more experiments are needed to understand the complex nature of persister formation. A recurrent scheme for inducing the persistent state involves toxins from chromosomal toxin–antitoxin (TA) systems (e.g., Dörr et al. 2010; Kim and Wood 2010; Maisonneuve et al. 2011). In unstressed cells, antitoxins normally inhibit either translation or activity of their toxin counterparts. However, when stress occurs, the inhibiting effect is released and cellular processes are impeded by the action of one or several toxins. The different TA systems are classified according to the specific mechanism by which the antitoxin inhibits the toxin directly, or its synthesis. In total, six different TA system types have been described so far (reviewed in Page and Peti 2016). Translational repression of toxin mRNA by an antisense RNA (type I) and inhibition of toxin activity by an antitoxin via protein–protein interaction (type II) are the predominant mechanisms. The first persistencerelated toxin gene was hipA in Escherichia coli (Moyed and Bertrand 1983). HipA belongs to the type II TA system HipAB. Its mode of action was recently deciphered: HipA phosphorylates glutamyl-tRNA synthetase, causing uncharged tRNA accumulation, thereby triggering the synthesis of the alarmone (p)ppGpp (Germain et al. 2013, 2015; Kaspy et al. 2013). Accumulation of (p) ppGpp results in activation of Lon protease, which, in turn (...truncated)


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs00294-017-0710-y.pdf

Bork A. Berghoff, E. Gerhart H. Wagner. RNA-based regulation in type I toxin–antitoxin systems and its implication for bacterial persistence, Current Genetics, 2017, pp. 1-6, DOI: 10.1007/s00294-017-0710-y