Daptomycin versus Friulimicin B: in-depth profiling of Bacillus subtilis cell envelope stress responses

Abstract

The related lipo(depsi)peptide antibiotics daptomycin and friulimicin B show great potential in the treatment of multiply resistant gram-positive pathogens. Applying genome-wide in-depth expression profiling, we compared the respective stress responses of Bacillus subtilis. Both antibiotics target envelope integrity, based on the strong induction of extracytoplasmic function sigma factor-dependent gene expression. The cell envelope stress-sensing two-component system LiaRS is exclusively and strongly induced by daptomycin, indicative of different mechanisms of action in the two compounds.

FIG. 1.

Chemical structures of the lipodepsipeptide antibiotic daptomycin (A) and the lipopeptide antibiotic friulimicin B (B).

FIG. 2.

Synthesis patterns of marker proteins after induction with daptomycin (DAP) or friulimicin B (FRI) compared to patterns of untreated control cells. Details from the two-dimensional gels of the cytoplasmic proteome (“spot albums” of marker proteins) are shown for two time points postinduction with each of two compounds. (A) Proteins induced by both antibiotics. (B) Daptomycin-specific spots. (C) Friulimicin B-specific spots. See text for details.

FIG. 3.

Schematic representation of the regulatory networks orchestrating the daptomycin (DAP) and friulimicin B (FRI) stress responses. The thickness of the arrows corresponds to the strength of induction of the given regulators (see text and Table 1 for details). TCS, two-component system.