Thiolactomycin, a new antibiotic. IV. Biological properties and chemotherapeutic activity in mice.

Abstract

The new thiolactone antibiotic, thiolactomycin, is rapidly absorbed in rats when administered either orally or by intramuscular injection. A peak in concentration of the drug is reached in the blood and in various visceral organs within 15 minutes after administration. The concentration decreases rather rapidly and about 51-69 % of the drug is excreted in urine during the first 24 hours.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 was more effective than carbenicillin in treating experimental acute urinary tracts infected with S. marcescens.Also, in mice whose immunodefense was decreased by treatment with cyclophosphamide, thiolactomycin was more effective than carbenicillin against S. marcescens challenge.

Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

“…1) (10,12,14). Despite its modest affinity, the antibiotic TLM has been shown to possess efficacy in Serratia marcescens and Klebsiella pneumoniae murine models of infection (15). Importantly, TLM inhibits both classes of condensing enzymes, the KAS I/II enzymes (FabB/F in Escherichia coli, KasA/B in M. tuberculosis) that participate in the fatty acid elongation cycle and the FAS-II-initiating KAS III enzymes (FabH) (16 -18).…”

Inhibition of β-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin

“…TLM is a unique thiolactone molecule that reversibly inhibits type II, but not type I, fatty-acid synthases (31,32) and is effective against many pathogens. The antibiotic is not toxic to mice and affords significant protection against urinary tract and intraperitoneal bacterial infections (33). TLM is active against Gram-negative anaerobes associated with periodontal disease (34) and exhibits antimycobacterial action by virtue of its inhibition of mycolic acid synthesis (35).…”

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

“…Naturally occurring (5R)-thiolactomycin (TLM, 46) exhibits potent in vivo activity against many pathogenic bacteria, including Gram-negative and Gram-positive bacteria and M. tuberculosis (114)(115)(116). TLM inhibits bacterial and plant type II fatty acid synthases (FAS-II) but not mammalian or yeast type I fatty acid synthases (FAS-I) (117).…”