Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus.

ALBANESI, D., REH, G., GUERIN, M.E., SCHAEFFER, F., DEBARBOUILLE, M. BUSCHIAZZO, A. SCHUJMAN, G.E., DE MENDOZA, D. AND ALZARI, P.M.

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013 vol. 9 p. 1 - 11

1553-7366

An opportunistic Gram-positive pathogen, Staphylococcus aureus is a major threat to humans and animals, being responsible for a variety of infections ranging from mild superficial to severe infections such as infective endocarditis, septic arthritis, osteomyelitis and sepsis. The increasing resistance of S. aureus against most current antibiotics emphasizes the need to develop new approaches to control this important pathogen. The lipid biosynthetic pathway is one appealing target actively pursued to develop anti-Staphylococcal agents. Despite its potential biomedical importance, however, little is known about the signaling mechanisms that allow S. aureus to control its phospholipid content. In order to shed light on this fundamental mechanism, we studied S. aureus FapR (SaFapR) a transcription factor that senses the levels of malonyl-CoA, a key intermediate in fatty acid biosynthesis, and modulates the expression of genes involved in fatty acid and phospholipid biosynthesis. Our studies of SaFapR uncovered the mechanistic basis of a complex biological switch that controls membrane lipid homeostasis in S. aureus. We also discovered that disruption of the ability of SaFapR to recognize malonyl-CoA, the ligand that controls SaFapR binding to DNA, compromises S. aureus viability, thus revealing new opportunities for the development of antibiotics against this major human pathogen.