Wake me when it’s over – Bacterial toxin–antitoxin proteins and induced dormancy

Abstract

Toxin-antitoxin (TA) systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune response. During normal conditions, the antitoxin components prevent toxins from interfering with metabolism and arresting growth; however, toxin activation enables microbes to remain dormant through unfavorable conditions that might continue over millions of years. Intense investigations have revealed a multitude of mechanisms for both regulation and activation of TA systems, which are abundant in pathogenic microorganisms. This minireview provides an overview of the current knowledge regarding type II TA systems along with their clinical and environmental implications.

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

“…The TA genes on the plasmid are often horizontally transferred, conferring antibiotic resistance and virulence in pathogenic bacteria. Additionally, the TA genes on chromosomes of various prokaryotes show alternative broad cellular functions that respond to diverse stressful environments such as nutrient deficiency, antibiotic treatment, bacteriophage infection, immune system attack, oxidative stress, and high temperature [11,12]. Depending on the types of TA systems, the activation of the toxin can eventually cause slow cell growth or cell cycle arrest, as is most frequently found in dormant persister cells [6,13,14,15].…”

“…Such a system is commonly composed of toxin and antitoxin proteins that are expressed independently in the same operon but form a stable complex under normal growth condition, which renders the toxin post-translationally inactive [7,12,90,91,92]. In most cases, the TA complex or the antitoxin alone can bind to the corresponding TA operon and repress its transcription.…”

Environmental conditions define the energetics of bacterial dormancy and its antibiotic susceptibility

“…The physiological state induced by bacteriostatic drugs is another example of dormancy, as these drugs cause growth arrest, but cells remain viable. Cells can stop growing in response to internal stimuli too, for example due to DNA damage Kreuzer [2013] or the accumulation of toxins in the cytoplasm Coussens and Daines [2016].…”

Crystal structure of proteolyzed VapBC and DNA‐bound VapBC from Salmonella enterica Typhimurium LT2 and VapC as a putative Ca 2+ ‐dependent ribonuclease

“…When a daughter cell loses the parental plasmid encoding TA operons, the daughter cell is killed by the toxin that is released from the TA complex when the labile antitoxin is degraded . Since the first discovery of TA operons in prokaryotes, TA operons in various bacterial chromosomes have been reported, and identification of the abundance of TA operons on the chromosome of prokaryotes has generated the idea that TA operons might have other biological roles, such as multidrug tolerance, biofilm formation, and arrest of cellular growth under harsh conditions, such as nutrient deficiency, antibiotic treatment, bacteriophage infection, immune system attack, oxidative stress, and high temperature …”

“…TA operons in prokaryotes, TA operons in various bacterial chromosomes have been reported, 2 and identification of the abundance of TA operons on the chromosome of prokaryotes has generated the idea that TA operons might have other biological roles, such as multidrug tolerance, [3][4][5] biofilm formation, 6 and arrest of cellular growth 7 under harsh conditions, such as nutrient deficiency, antibiotic treatment, bacteriophage infection, immune system attack, oxidative stress, and high temperature. 8,9 TA pairs are generally classified into six types, according to the genetic structure and regulation modes of the antitoxin molecules. [10][11][12] In the type I and III TA systems, the antitoxins are RNA molecules that directly inhibit translation or regulate toxin activities.…”