Susceptibility of Two Gram‐Positive Pathogens to Fatty Acid Synthesis Inhibitors

Bacterial fatty acid synthesis (FASII) is an attractive target for treatment of Gram‐positive pathogens. The value of FASII inhibitors was recently questioned based on the ability of Streptococcus agalactiae to circumvent inhibition by utilizing exogenous fatty acids (FA) for phospholipid synthesis. This study compares the efficacy of FASII inhibitors against Staphylococcus aureus and Streptococcus pneumoniae grown in media containing FA. Exogenous FA overcame inhibition in S. pneumoniae, but not S. aureus. Neither the substrate specificities of the acyltransferases, nor the divergent modes of transcriptional regulation accounted for this difference. Exogenous FA strongly suppressed malonyl‐CoA production in S. pneumoniae but not S. aureus , indicating biochemical regulation at the acetyl‐CoA carboxylase in S. pneumoniae is the key difference between the two species. The lack of feedback regulation of malonyl‐CoA formation results in the accumulation of short chain acyl‐ACP and a block in exogenous FA uptake in S. aureus treated with FASII inhibitors. The ability of exogenous FA to biochemically inhibit the initiation of FASII determines whether FASII inhibitors will be effective against Gram‐Positive bacteria in the presence of exogenous FA. Supported by NIH GM034496 and ALSAC.