Although, a large proportion of pathogenic bacteria gets eliminated from hosts after antibiotic treatment, a fraction of population confronts against such effects and undergoes growth arrest to form persisters. Persistence in bacteria is a dormant physiological state where cells escape the effects of antimicrobials as well as other host immune defences without any genetic mutations. The state of dormancy is achieved through various complex phenomena and it is known that a gene pair named as toxin–antitoxin (TA) acts as a key player of persister cell formation where the toxin is activated either stochastically or after an environmental insult, thereby silencing the physiological processes. However, the controversial role of TA modules in persister cell formation has also been documented with reasonable clarity. Persisters may revert back from state of quiescence and regrow when conditions become favourable for their propagation. Therefore, the elimination of dormant bacteria is crucial, and currently, research interest is highly focussed on developing several antipersister strategies that may kill persister bacteria by targeting different molecules. It is worth examining these targets to develop appropriate therapeutic interventions against bacterial infections and it is believed that earmarking TA system can be a novel approach for resuscitation of persisters. In this review, we discussed the role of TA modules in mediating persistence with highlighting on the debatable issues regarding contribution of these modules in dormant bacteria formation. Furthermore, we discussed if these modules in bacteria can be targeted for successful elimination of dormant persister cells.
Toxin-antitoxin (TA) modules are two component “addictive” genetic elements found on either plasmid or bacterial chromosome, sometimes on both. TA systems perform a wide range of functions like biofilm formation, persistence, programmed cell death, phage abortive infection etc. Salmonella has been reported to contain several such TA systems. However, the hemolysin expression modulating protein (Hha) and its adjacent uncharacterized hypothetical protein TomB (previously known as YbaJ), have not been listed as a TA module in Salmonella. In this study we established that Hha and TomB form a bonafide TA system where Hha serves as a toxin while TomB functions as an antitoxin. Interestingly, the toxicity of Hha was conditional causing cell death under acid stress. The antitoxin attenuated the toxicity of Hha by forming a TA complex through stable interactions. The Hha-TomB TA system was found to increase persistence and inhibit programmed cell death under antibiotic stress where a phenotypically diverse population expressing differential level of TA components was observed. Therefore we propose that Hha and TomB prevent cells from committing suicide thereby promoting persister cell formation.
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