Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence

Here, we identified a long-chain acyl-CoA-responsive transcriptional repressor, FdmR, as the key regulator of mycobacterial fatty acid catabolism. We employed ChIP-Seq to identify the genomic binding regions for FdmR. FdmR was found to bind upstream of fadA2, fabG4, fadE24, fixA, MMAR_1683, fadE5, icl, desA3, desA3_1, and MMAR_2730.We then demonstrated that FdmR acts as a valve to direct the fatty acid flux from ß-oxidation towards lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. This regulatory mechanism enables a high rate of cell growth with modest consumption of fatty acid substrates. Overall design: The 10% sonicated DNA was stored and named “Input”, 80% was used in immunoprecipitation reactions with Monoclonal ANTI-FLAG® M2 antibody (Sigma) and named “IP”, and 10% was incubated with rabbit IgG (Cell Signaling Technology) as a negative control and named “IgG”, respectively. No biological replicates.