A Decrease in Fatty Acid Synthesis Rescues Cells with Limited Peptidoglycan Synthesis Capacity

Understanding how a bacterium coordinates cell envelope synthesis is essential to fully appreciate how bacteria grow, divide, and resist cell envelope stresses, such as beta-lactam antibiotics. Balanced synthesis of the peptidoglycan cell wall and the cell membrane is critical for cells to maintain shape and turgor pressure and to resist external cell envelope threats. Proper synthesis and maintenance of a multilayered cell envelope are critical for bacterial fitness. However, whether mechanisms exist to coordinate synthesis of the membrane and peptidoglycan 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 penicillin-binding proteins (aPBPs). We previously described mutant strains limited in their capacity for PG synthesis due to a loss of aPBPs and an inability to compensate by upregulation of 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 (FAS) genes. Consistent with fatty acid limitation mitigating cell wall synthesis defects, inhibition of FAS by cerulenin also restored growth of PG-limited cells. Moreover, cerulenin can counteract the inhibitory effect of beta-lactams in some strains. 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 physiological mechanism to reduce membrane synthesis when PG synthesis is impaired.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 beta-lactam antibiotics. Balanced synthesis of the peptidoglycan cell wall and the cell membrane is critical for cells to maintain shape and turgor pressure and to resist external cell envelope threats. Using Bacillus subtilis, we show that cells deficient in peptidoglycan synthesis can be rescued by compensatory mutations that decrease the synthesis of fatty acids. Further, we show that inhibiting fatty acid synthesis with cerulenin is sufficient to restore growth of cells deficient in peptidoglycan synthesis. Understanding the coordination of cell wall and membrane synthesis may provide insights relevant to antimicrobial treatment.

Automated summary

Understanding the coordination of cell wall and membrane synthesis is crucial for understanding bacterial growth, division, and resistance to cell envelope stresses. Balanced synthesis of the peptidoglycan cell wall and the cell membrane is critical for maintaining cell shape and pressure. In Bacillus subtilis, a loss of class A penicillin-binding proteins leads to impaired peptidoglycan synthesis, and compensatory mutations that decrease fatty acid synthesis can restore growth. Inhibiting fatty acid synthesis with cerulenin can also restore growth of the PG-limited cells and counteract the effects of beta-lactam antibiotics.