Proteolytically Coordinated Activation of Toxin-Antitoxin Modules

Abstract

Chronic bacterial infections present a serious threat to the health of humans by decreasing life expectancy and quality. Resilience of these populations is closely linked to a small fraction of persister cells that are capable of surviving a wide range of environmental stressors that include starvation, DNA damage, heat shock, and antibiotics. In contrast to inherited resistance, persistence arises from a rare and reversible phenotypic change that protects the cell for one or a few generations. The frequency and character of persistence is controlled in part by the dynamics of numerous toxin-antitoxin (TA) modules, operons with an evolutionarily conserved motif including a toxin that slows cell growth and an antitoxin that can neutralize the toxin. While many such modules have been identified and studied in a wide range of organisms, relatively little consideration of the interactions between multiple TA modules within a single host has been made. Particularly, a multitude of different protein-based antitoxin species are known to be actively degraded by a limited number of shared proteolytic pathways, strongly suggesting interaction via competition between antitoxins for degradation machinery. Here we present a theoretical understanding of the dynamics of multiple TA modules whose activity is coupled through either proteolytic activity, a toxic effect on cell growth rate, or both. We also present a generalizable theoretical mechanism by which a toxic state is tunable by regulation of proteolysis. Such regulation or indirect coordination between multiple TA modules may be at the heart of the flexibility and robustness observed for bacterial persistence.