A decrease in fatty acid synthesis rescues cells with limited peptidoglycan synthesis capacity

Proper synthesis and maintenance of a multilayered cell envelope is critical for bacterial fitness. However, whether genetic mechanisms exist to coordinate synthesis of the membrane and peptidoglycan envelope layers is unclear. In Bacillus subtilis, synthesis of peptidoglycan (PG) during cell elongation is mediated by an elongasome complex acting in concert with class A PBPs (aPBPs). We previously described mutant strains limited in their capacity for PG synthesis due to a loss of aPBPs and an inability to upregulate elongasome function. Growth of these PG-limited cells can be restored by suppressor mutations predicted to decrease membrane synthesis. One suppressor mutation leads to an altered function repressor, FapR*, that functions as a super-repressor and leads to decreased transcription of fatty acid synthesis genes. Consistent with fatty acid limitation mitigating cell wall homeostasis defects, inhibition of FAS by cerulenin also restored growth of PG-limited cells. Moreover, cerulenin rescued the growth of wild-type (WT) cells in the presence of otherwise inhibitory concentrations of β-lactams. These results imply that limiting PG synthesis results in impaired growth, in part, due to an imbalance of PG and cell membrane synthesis and that B. subtilis lacks a robust genetic mechanism to coordinate the balanced synthesis of these two envelope layers. Importance Understanding how a bacterium coordinates cell envelope synthesis is essential to fully appreciate how bacteria grow, divide, and resist cell envelope stresses such as β-lactam antibiotics. The balance between the peptidoglycan cell wall and the essential plasma membrane structure must be maintained for the cell to maintain shape, turgor pressure and resist external cell envelope threats. Using Bacillus subtilis, we show that cells deficient in peptidoglycan synthesis can be rescued by compensatory mutations which decrease the synthesis of fatty acids. Further, we show that inhibiting fatty acids synthesis with cerulenin is sufficient to reduce susceptibility to β-lactams. Understanding the coordination of cell wall and plasma membrane synthesis may provide insights relevant to antimicrobial treatment.