Drug Discovery Opinion

DDO Limited – Consultancy for Biotech and Pharma

Mar 13 2009

Evidence that FASII is Dispensable

Posted by SR in News, tags: antibacterial

Whereas mammalian fatty acid synthase (FASI) is a multidomain, multifunctional homodimeric protein which carries out all of the enzymatic steps needed for de novo synthesis of long chain fatty acids, bacterial fatty acid synthesis is carried out by a number of discrete enzymes, collectively known as FASII. This difference between FASI and FASII has led to the identification of FASII as a target for antibiotic therapy. The hypothesis is strengthened by the activities of the antiseptic, triclosan, the anti-Mycobacterium tuberculosis agent, isoniazid, and the antifungal antibiotic, cerulenin, which are believed to act primarily by inhibiting steps in the FASII pathway. The natural products, platensimycin and platensin, have also been shown to exhibit broad spectrum Gram-positive antibacterial activity and to inhibit fatty acid biosynthesis.

s. agalactiae A recently published letter in the journal Nature, however, suggests that inhibition of FASII as an approach to antimicrobial therapy may be fundamentally flawed. The new study showed that major Gram-positive pathogens, such as streptococci, enterococci and staphylococci, were able to grow in the presence of FASII pathway inhibitors, cerulenin and triclosan, if supplied with exogenous fatty acids at levels that would be present in human serum. Using Streptococcus agalactiae – an opportunistic pathogen that can cause serious meningitis in newborns – as a model, the authors demonstrated that the unsaturated fatty acids, linoleic acid and oleic acid, but not the saturated fatty acids, palmitic acid and stearic acid, were able to overcome the inhibitory effect of cerulenin treatment.

linoleic acid The authors also demonstrated that when S agalactiae is grown in the presence of serum, there is an overall decrease in FASII gene expression. In further experiments, deletion mutants were used to demonstrate that FASII enzymes are dispensable in vivo during S agalactiae infection. Growth of all deletion mutants was severely restricted in standard Todd Hewitt (TH) medium, but all grew comparably with wild type strains in serum or in the presence of added oleic acid or linoleic acid. The mutant strains were also as virulent as wild type strains in animal models, even if the animals were treated with the hypolipidemic agent, fenofibrate. The authors believe that drugs targeting FASII would be ineffective in natural infections unless the bacteria had a requirement for specific fatty acids not present in serum.