FIG 7.
Model for intersecting control of the stringent response and FASII inhibition in S. aureus. (Left) Stringent response induction leads to GTP depletion, which in turn modulates gene expression to prepare for starvation (20, 31). We showed that inhibition of FASII also leads to GTP depletion, pointing to an intersecting link between these pathways. Both conditions activate stringent response sensors (PilvD-lacZ, PoppB-lacZ, and PcshA-lacZ) and lower malonyl-CoA (mal-CoA) pools, such that FapR (for which mal-CoA acts as anti-repressor) exerts repression (13). As a consequence, genes under FapR control, including plsX and plsC, remain repressed, blocking phospholipid synthesis. Both stringent response induction and FASII inhibition during the latency phase lead to membrane synthesis arrest. (Right) Upon FASII adaptation, GTP levels are restored. accBC expression is restored to normal, and mal-CoA levels are increased, leading to FapR derepression. In consequence, PlsX and PlsC are both increased, such that phospholipid synthesis resumes. Red and green arrows and circled metabolites correspond to functions analyzed in this study. * refers to activities based on previous studies.