Characterization of the Induction and Cellular Role of the BaeSR Two-Component Envelope Stress Response of Escherichia coli

Abstract

The bacterial cell envelope is the interface between a bacterium and its environment and is constantly exposed to environmental changes. The BaeSR two-component system regulates one of six envelope stress responses in Escherichia coli and is induced by spheroplasting, overexpression of the pilin subunit PapG, and exposure to indole. The known BaeR regulon is small, consisting of eight genes, mdtABCD-baeSR, acrD, and spy, two of which encode the BaeSR two-component system itself. In this study, we investigated the molecular nature of the BaeS-inducing cue and the cellular role of the BaeSR envelope stress response. We demonstrated that at least two flavonoids and sodium tungstate are novel inducers of the BaeSR response. Interestingly, flavonoids and sodium tungstate led to much stronger induction of the BaeSR response in an mdtA efflux pump mutant, while indole did not. These findings are consistent with the hypothesis that flavonoids and sodium tungstate are natural substrates of the MdtABC efflux pump. Indole has recently been implicated in cell-cell signaling and biofilm repression through a putative interaction with the LuxR homologue SdiA. Using genetic analyses, we found that induction of the BaeSR response by indole occurs via a pathway separate from the SdiA biofilm pathway. Further, we demonstrated that the BaeSR response does not influence biofilm formation, nor is it involved in indole-mediated inhibition of biofilm formation. We hypothesize that the main function of the Bae response is to upregulate efflux pump expression in response to specific envelope-damaging agents.

Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance inSalmonellaTyphimurium

“…Because antimicrobial agents may be potentiated by ROS (2), the coordinate expression of drug and iron citrate efflux systems could both remove toxic agents and ameliorate their cytotoxic actions. MdtABC and IceT expression are regulated by the BaeSR twocomponent regulatory system, which has been implicated in extracytoplasmic stress resistance in E. coli (30,44). Although the mechanism of BaeSR activation remains to be elucidated, the present study shows that nitrosative stress and dysregulation of iron metabolism lead to expression of the mdtABC iceT baeSR operon, consistent with a role in defense against free ironmediated cytotoxicity and host-associated stresses, whereas work by others has shown induction of expression by the antibiotic ciprofloxacin (45).…”

“…(29)(30)(31). A role for mdtABC in resistance to novobiocin, bile salts, deoxycholate, and β-lactam antibiotics has been demonstrated, and a role in transport of flavenoids and sodium tungstate has been suggested (29)(30)(31)(32)(33). MdtD is a predicted cytoplasmic membrane protein with 12-14 transmembrane domains.…”

“…This operon encodes a resistance-nodulation-division (RND) drug efflux pump (MdtABC), an uncharacterized transporter in the major facilitator superfamily (MFS) group (MdtD), and a twocomponent regulatory system (BaeSR) that has been shown to regulate expression of its own operon as well as the multidrug transporter acrD, periplasmic chaperone spy, and genes of unknown function, yicO and ygcL. (29)(30)(31). A role for mdtABC in resistance to novobiocin, bile salts, deoxycholate, and β-lactam antibiotics has been demonstrated, and a role in transport of flavenoids and sodium tungstate has been suggested (29)(30)(31)(32)(33).…”

“…A variety of inducing conditions have been suggested for the mdtABCD baeSR operon (30,(33)(34)(35). We determined whether host cell-derived antimicrobial mediators such as nitric oxide (NO·), superoxide, or hydrogen peroxide, which can target iron centers and promote Fenton chemistry, are capable of inducing mdtABCD baeSR expression.…”

BaeSR, Involved in Envelope Stress Response, Protects against Lysogenic Conversion by Shiga Toxin 2-Encoding Phages

“…Some factors, such as indole, sodium tungstate, or zinc (27)(28)(29), induce BaeSR response and should cause interference with the acquisition of Stx phages by their potential host strains. For instance, zinc has been reported to inhibit virulence traits in pathogenic E. coli and, in particular, Stx phage induction (30).…”