FIG 5.

Proposed model for the regulatory interplay between the exogenous and endogenous fatty acid supply for phospholipid biosynthesis and its consequences for 2CCA-1 resistance. (A) Under conditions of low extracellular fatty acid availability, fakB3 expression is enhanced by the presence of FabT. Since FabT does not bind to the fakB3 promoter, the regulation is likely conferred indirectly by yet-unknown mediators. The main supply of phospholipid building blocks comes from the FASII system, which is subjected to feedback inhibition by FabT with long-chain acyl ACP1 as the corepressor (15). (B) Upon availability of abundant extracellular fatty acids, FabT:acyl-ACP2 mediates the repression of the fab operon (16–18). FabT also influences the repression of fakB3, resulting in decreased incorporation of polyunsaturated fatty acids (16) into the membrane, which could ensure its homeostasis. How fakB3 repression is influenced by FabT remains to be identified. (C) Mutants with deletions of fakB3 are resistant to 2CCA-1. A deleterious mutation in fabT abolishes the enhanced transcription of fakB3 in medium with a low extracellular fatty acid concentration. Thus, in a fabT mutant, 2CCA-1 incorporation by fakB3 could be greatly reduced, so that the mutant resists higher 2CCA-1 concentrations than a wild-type pneumococcal strain.