Disease relevance of TLM

• The biochemical basis for the inhibition of fatty acid biosynthesis in Escherichia coli by the antibiotic thiolactomycin was investigated [1].
• Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis [2].
• Leucine is the only other amino acid found at position 390 in nature, and the Staphylococcus aureus FabF protein, which contains this substitution, was sensitive to TLM [3].
• Using a flexible synthesis, families of TLM structural analogues were obtained that possess selective FAS activity and display anticancer and weight loss effects [4].
• These studies identify thiolactomycin as a promising template for the development of new selective cancer and obesity treatments [4].

High impact information on TLM

• Furthermore, PfFabBF was shown to be sensitive to cerulenin and thiolactomycin, known inhibitors of beta-ketoacyl-ACP synthases [5].
• In addition, purified mtFabH was sensitive to thiolactomycin and resistant to cerulenin in an in vitro assay [6].
• The resulting transformants, as well as previously published M. tuberculosis strains with multicopy inhA or kasAB plasmids, were tested for their resistance to INH, ethionamide (ETH) or thiolactomycin (TLM) [7].
• In contrast, the kasA plasmid conferred no increased resistance to INH or ETH in any of the five strains, but it did confer resistance to thiolactomycin, a known KasA inhibitor [7].
• Modeling of TLM binding in mtKasB shows that the drug fits the active site poorly and results of enzyme inhibition assays using TLM analogues are wholly consistent with our structural observations [8].

Chemical compound and disease context of TLM

• Signature gene expression profiles discriminate between isoniazid-, thiolactomycin-, and triclosan-treated Mycobacterium tuberculosis [9].
• Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme [10].

Biological context of TLM

• Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli [11].
• Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases [11].
• TLM resistance is associated with the upregulation of efflux pumps [3].
• Six independent TLM-resistant clones of strain ANS1 were isolated, and all possessed the same missense mutation in the fabB gene (T1168G) that directed the expression of a mutant protein, FabB(F390V) [3].

Anatomical context of TLM

• It has recently been demonstrated that type II fatty acid biosynthesis occurs in the plastid of Plasmodium falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan and thiolactomycin restrict their growth [12].
• Antibiotic thiolactomycin, which inhibits bacterial O-acetyltransferase, did not affect the activation by hamster and rat cytosol, indicating the difference in property between bacterial and mammalian enzymes [13].
• Though the in vitro effect of thiolactomycin is moderate, it effectively protected mice challenged intraperitoneally with several strains of S. marcescens and K. pneumoniae and more effective than carbenicillin in treating experimental acute urinary tracts infected with S. marcescens [14].

Associations of TLM with other chemical compounds

• We have developed a mathematical model, based on the expression of 21 genes, which is able to perfectly discriminate between isoniazid-, thiolactomycin-, or triclosan-treated M. tuberculosis [9].
• Furthermore, Trypanosoma brucei has recently been demonstrated to use type II fatty acid biosynthesis for myristate synthesis and to be susceptible to thiolactomycin [12].
• Some known antibiotics that target the FAS II system include triclosan, isoniazid, and thiolactomycin [15].

Gene context of TLM

• Therefore, a tolC knockout mutant (strain ANS1) was constructed to eliminate the contribution of type I secretion systems to TLM resistance [3].
• Whereas thiolactomycin was not a substrate of the MexCD-OprJ pump expressed in a delta(mexAB-oprM) nfxB mutant, cerulenin was efficiently effluxed by the MexCD-OprJ system [16].
• In addition, acetyl-CoA:ACP transacylase activity in strain CDM5 was resistant to inactivation by thiolactomycin suggesting that the acetoacetyl-ACP synthase also catalyzes this transacylation reaction [1].
• Another subclass of TLM derivatives (23b-d, 31a) exhibits FAS activity (IC(50) = <or=15 microg/mL), causes weight loss (>5%), and is cytotoxic to cancer cells (IC(50) < 38 microg/mL) [4].
• Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum [17].

Analytical, diagnostic and therapeutic context of TLM

• The new thiolactone antibiotic, thiolactomycin, is rapidly absorbed in rats when administered either orally or by intramuscular injection [14].

References