Toxin-antitoxins and sigma factors may optimize the fitness of free-living bacteria throughout the life cycle via an integrated nutrient-responsive cybernetic system.

Toxin-antitoxin systems (TASs) are ubiquitous in the chromosomes of free-living bacteria, yet their primary biological function remains poorly understood. Bacteria reproduce exponentially via 2 growth kinetics and thus must respond to changing nutrient availability to reproduce rapidly during short periods of feast and survive during long periods of famine. Type II TASs represent stable enzyme-unstable inhibitor systems that are regulated by reversible competitive inhibition, which allows them to efficiently produce pleiotropic effects on prokaryotic cells in a continuous (analogue) manner due to varying concentrations of free toxin throughout the life cycle. A nutrient-responsive cybernetic system (NRCS) model is proposed where intracellular nutrient concentration feeds back to control the emergent properties of growth, death and growth/death arrest, which results in a novel fitness strategy termed K Sensing and Control. When nutrients become limiting, alternative general stress response sigma factors Ϭ and Ϭ regulate the expression of hundreds of genes that may control the transformation of vegetative bacteria into coccoid, stress-tolerant 'motherspores'. An integrated NRCS model is presented that shows how TASs and sigma factors may work in concert to efficiently regulate population dynamics, cellular physiology and cellular differentiation throughout the life cycle, which optimizes the biological fitness of free-living bacteria.