Abstract
The rationale for the pursuit of bacterial type 2 fatty acid synthesis (FASII) as a target for antibacterial drug discovery in Gram-positive organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. The regulation of FASII by extracellular fatty acids was examined in Staphylococcus aureus and Streptococcus pneumoniae, representing two important groups of pathogens. Both bacteria use the same enzymatic tool kit for the conversion of extracellular fatty acids to acyl-acyl carrier protein, elongation, and incorporation into phospholipids. Exogenous fatty acids completely replace the endogenous fatty acids in S. pneumoniae but support only 50% of phospholipid synthesis in S. aureus. Fatty acids overcame FASII inhibition in S. pneumoniae but not in S. aureus. Extracellular fatty acids strongly suppress malonyl-CoA levels in S. pneumoniae but not in S. aureus, showing a feedback regulatory system in S. pneumoniae that is absent in S. aureus. Fatty acids overcame either a biochemical or a genetic block at acetyl-CoA carboxylase (ACC) in S. aureus, confirming that regulation at the ACC step is the key difference between these two species. Bacteria that possess a stringent biochemical feedback inhibition of ACC and malonyl-CoA formation triggered by environmental fatty acids are able to circumvent FASII inhibition. However, if exogenous fatty acids do not suppress malonyl-CoA formation, FASII inhibitors remain effective in the presence of fatty acid supplements.
Highlights
(FASII) as a target for antibacterial drug discovery in Gram-positive organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids
The differences in the biochemical regulation of acetyl-CoA carboxylase (ACC) by exogenous fatty acids account for the responses of S. aureus and S. pneumoniae to FASII inhibitors (Fig. 4E)
In S. pneumoniae fatty acid supplements potently suppress the formation of malonyl-CoA by ACC to eliminate FASII activity
Summary
(FASII) as a target for antibacterial drug discovery in Gram-positive organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. These discoveries, coupled with the realization that two widely used antibacterial agents, triclosan [17, 18] and isonaizid [19], target FabI, stimulated the development of small-molecule FabI inhibitors [3] These inhibitors were developed to target S. aureus because other groups of Gram-positive pathogens, exemplified by Streptococcus pneumoniae, do not express an FabI but rather carry out the enoyl-ACP reduction using the unrelated FabK flavoprotein [20]. Balemans et al [24] were unable to show that fatty acids rescued S. aureus treated with a FabI inhibitor, but Brinster et al [28] countered by showing that S. aureus can incorporate exogenous fatty acids and have constructed a S. aureus fabI knockout that is a fatty acid auxotroph This article addresses this debate by showing that exogenous fatty acids stringently repress acetyl-CoA carboxylase (ACC) activity in Gram-positive bacteria like S. pneumoniae, allowing fatty acid supplements to replace endogenous fatty acids completely. S. aureus lacks this regulatory control system, and the inability of exogenous fatty acids to shut off de novo biosynthesis accounts for their sensitivity to FASII inhibitors even in the presence a fatty acid supplement
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