Competitive behaviors in Serratia marcescens are coordinately regulated by a lifestyle switch frequently inactivated in the clinical environment

Opportunistic bacterial pathogens must compete with other bacteria and switch between host- and environment-adapted states. Type VI secretion systems (T6SSs) occur widely in gram-negative bacteria and can efficiently kill neighboring competitors. We determined the distribution of T6SSs across the genus Serratia and observed that a highly conserved antibacterial T6SS is differentially active between closely related clinical isolates of Serratia marcescens. By combining genomic and experimental approaches, we identified a genus-core two-component system, BetR-Reg1-Reg2, that controls T6SS activity and exhibits frequent inactivating mutations, exclusively in S. marcescens isolates of clinical origin. This regulatory system controls a number of lifestyle-related traits at transcriptional and post-translational levels, including T6SS activity, antibiotic production, motility, and adhesion, with loss of BetR increasing virulence in an in vivo infection model. Our data support a model whereby this system represents a conserved, modular switch from sessile to pioneering and aggressive behavior, which is subject to selection pressure in clinical environments.