MmbR, a master transcription regulator that controls fatty acid β-oxidation genes in Mycolicibacterium smegmatis

An unusually high lipid content and a complex lipid profile are the most distinctive features of the mycobacterial cell envelope. However, our understanding of the regulatory mechanism underlying mycobacterial lipid metabolism is limited, and the major regulators responsible for lipid homeostasis remain to be characterized. Here, we identified MmbR as a novel master regulator that is essential for maintaining lipid homeostasis in Mycolicibacterium smegmatis. We found that MmbR controls fatty acid β-oxidation and modulates biofilm formation in Mycolicibacterium smegmatis. Although MmbR possesses the properties of nucleoid-associated proteins, it acts as a TetR-like transcription factor, directly regulating and intensively repressing the expression of a group of core genes involved in fatty acid β-oxidation. Furthermore, both long-chain acyl-Coenzyme A and fatty acids appear to regulate the signal molecules modulated by MmbR. The deletion of mmbR led to a significant reduction in intracellular fatty acid content and a decrease in the relative lipid composition of the biofilm. The lack of mmbR led to morphological changes in the mycobacterial colony, defects in biofilm formation and enhanced sensitivity to anti-tuberculosis drugs. Our study is the first to establish a link between the transcriptional regulation of fatty acid β-oxidation genes and lipid homeostasis in mycobacteria.