Heterogeneous cell wall homeostasis as a survival strategy in stationary phase: balancing cell growth, antibiotic production, and envelope stress response in Bacillus subtilis

The cell envelope is an essential yet highly dynamic structure that protects the bacterial cell from its environment. Maintaining its integrity throughout the growth cycle - even in the face of antibiotic threat - is absolutely essential for survival. While significant progress has been made in recent years on understanding envelope homeostasis during balanced growth, little is known on the regulatory and physiological adjustments in stationary phase. The goal of the project is to study how bacteria maintain cell envelope homeostasis during the complex differentiation cascade of Bacillus subtilis during stationary phase. Within this differentiation process, a subpopulation of cells produces antimicrobial peptides (AMPs) that not only interfere with cell wall biosynthesis of competing species, but also target subpopulations of B. subtilis cells in a process termed cannibalism. Since many AMPs inhibit active cell wall biosynthesis, it seems likely that only a subpopulation of cells that are still vegetative in stationary phase is susceptible to AMP action. Moreover, we previously showed that in stationary phase B. subtilis induces parts of the cell envelope stress response (CESR) to defend against AMP attack, but it does so only in a small subpopulation of cells (Dominguez-Escobar et al., 2014). However, to date it is unknown how the heterogeneous stationary phase traits of AMP production, cell growth and the induction of the CESR are correlated at the single cell level and how this would result in a concerted survival strategy in stationary phase. To study these questions, we combine experimental approaches from molecular biology with mathematical modeling approaches from theoretical physics. Ultimately, we would like to unravel the physiological relevance of phenotypic heterogeneity in cell envelope homeostasis and Lia-mediated CESR for stationary phase survival.