Bacterial toxin-antitoxin systems: Novel insights on toxin activation across populations and experimental shortcomings

The alarming rise in hard-to-treat bacterial infections is of great concern to human health. Thus, the identification of molecular mechanisms that enable the survival and growth of pathogens is of utmost urgency for the development of more efficient antimicrobial therapies. In challenging environments, such as presence of antibiotics, or during host infection, metabolic adjustments are essential for microorganism survival and competitiveness. Toxin-antitoxin systems (TASs) consisting of a toxin with metabolic modulating activity and a cognate antitoxin that antagonizes that toxin are important elements in the arsenal of bacterial stress defense. However, the exact physiological function of TA systems is highly debatable and with the exception of stabilization of mobile genetic elements and phage inhibition, other proposed biological functions lack a broad consensus. This review aims at gaining new insights into the physiological effects of TASs in bacteria and exploring the experimental shortcomings that lead to discrepant results in TAS research. Distinct control mechanisms ensure that only subsets of cells within isogenic cultures transiently develop moderate levels of toxin activity. As a result, TASs cause phenotypic growth heterogeneity rather than cell stasis in the entire population. It is this feature that allows bacteria to thrive in diverse environments through the creation of subpopulations with different metabolic rates and stress tolerance programs.