FIGURE 6.

CroRS regulates isoprenoid flux between cell wall biogenesis and aerobic respiration to maintain cell wall homeostasis in response to antimicrobial stress. In wild‐type Enterococcus faecalis CroRS confers tolerance to TXB‐induced cell killing by regulating isoprenoid flux using a dual mechanism. In response to TXB challenge, we hypothesise CroRS simultaneously reduces the capacity for aerobic respiration, and thus the demand for isoprenoids/demethylmenaquinone (DMK), by decreasing the expression of cytochrome bd (green box; CydA, CydB), while upregulating genes (purple boxes) involved in isoprenoid biosynthesis (i.e. mevalonate pathway and UPP synthase) and cell wall biogenesis (i.e. peptidoglycan, teichoic acids and Epa polysaccharide). In the absence of croRS, E. faecalis is susceptible to killing by TXB. However, proposed loss of function mutations in a heptaprenyl diphosphate synthase (yellow box; HppS) can partially rescue this phenotype. This supports our hypothesis that TXB tolerance can be conferred in E. faecalis through the control of isoprenoid flux from aerobic respiration to cell wall biogenesis.