This study thus presents FdmR as a potentially attractive target for chemotherapy.įatty acids are metabolized to meet the catabolic and anabolic needs of mycobacterial cells after conversion to their acyl-coenzyme A (acyl-CoA) derivatives ( 13, 14). These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase.

We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from β-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)–responsive repressor of genes involved in fatty acid degradation and modification. The mutant showed defective growth but high substrate consumption on fatty acids. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection.

Fdmr sathiyya