A systematic search for switch-like behavior in type II toxin-antitoxin systems.

Bistable switch-like behavior is a ubiquitous feature of gene regulatory networks with decision-making capabilities. Type II toxin-antitoxin (TA) systems are hypothesized to facilitate a bistable switch in toxin concentration that influences the dormancy transition in persister cells. However, a series of recent retractions has raised fundamental questions concerning the exact mechanism of toxin propagation in persister cells and the relationship between type II TA systems and cellular dormancy. Through a careful modeling search, we identify how sp: bistablilty can emerge in type II TA systems by systematically modifying a basic model for the RelBE system with other common biological mechanisms. Our systematic search uncovers a new combination of mechanisms influencing bistability in type II TA systems and explores how toxin bistability emerges through synergistic interactions between paired type II TA systems. Our analysis also illustrates how Descartes' rule of signs and the resultant can be used as a powerful delineator of bistability in mathematical systems regardless of application.

The PafBC-mediated response sensitizes a bistable DNA damage response in Mycobacteria.

Due to the genotoxically challenging environments in which they live in, Mycobacteria have a complex DNA damage repair system that is governed by two major DNA damage responses, namely, the LexA/RecA-dependent response and the newly characterized PafBC-mediated response (Müller et al., 2018). The LexA/RecA-dependent response is a well-known bistable response found in different types of bacteria, and the Mycobacteria-specific PafBC-mediated response interacts with and modifies the LexA/RecA-dependent response (Müller et al., 2018). The interaction between the LexA/RecA-dependent response and the PafBC-mediated response has not been characterized mathematically. Our analysis shows that the addition of the PafBC-mediated response sensitizes the overall DNA damage response, effectively lowering the DNA damage rate threshold for activation.

There and back again: consequences of biofilm specialization under selection for dispersal.

Experimental evolution paired with modern sequencing can be a powerful approach to identify the mechanisms by which bacteria adapt to discrete environmental conditions found in nature or during infections. We used this approach to identify mechanisms enabling biofilm specialists of the opportunistic respiratory pathogen Burkholderia cenocepacia to regain planktonic fitness. Seven mutants producing wrinkly (W) small-colony variants by mutations in the wrinkly-spreader operon (wsp) cluster, but with varying duration of biofilm adaptation, served as ancestors of this experiment. Following planktonic growth, each W ancestor produced smooth (S) mutants with distinct fitness effects across planktonic, biofilm, and dispersal-phase environments. The causes of the S phenotype traced to mutations in three gene clusters: wsp, Bcen2424_1436, an uncharacterized two-component transcriptional regulator which appears to be critical for wsp signaling, and a cohort of genes involved in polysaccharide synthesis. The genetic pathway from W to S also associated with evolutionary history in the biofilm environment. W mutants isolated from long-term biofilm selection usually produced S types via secondary wsp mutations, whereas S types evolved from less adapted W ancestors by a wider scope of mutations. These different genetic pathways to suppress the W phenotype suggest that prolonged biofilm adaptation limits routes to subsequent planktonic adaptation, despite common initial mechanisms of biofilm adaptation. More generally, experimental evolution can be used as a nuanced screen for gain-of-function mutations in multiple conditions that illustrate tensions that bacteria may face in changing environments or hosts.