N-Thiolated β-Lactams: Studies on the Mode of Action and Identification of a Primary Cellular Target in S. aureus

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 6; pp. 2453 - 2467
• Main Authors: Revell, Kevin D., Heldreth, Bart, Long, Timothy E., Jang, Seyoung, Turos, Edward
• Format: Journal Article
• Language: English
• Published: 20.12.2006
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.12.027

This study focuses on the mechanism of action of N -alkylthio β-lactams, a new family of antibacterial compounds that show promising activity against Staphylococcus and Bacillus microbes. Previous investigations have determined that these compounds are highly selective towards which bacteria they target, and possess completely unprecedented structure-activity profiles for a β-lactam antibiotic. Unlike penicillin, which inhibits cell wall crosslinking proteins and affords a broad spectrum of bacteriocidal activity, these N -thiolated lactams are bacteriostatic in their behavior and act through a different mechanistic mode. Our current findings indicate that the compounds react rapidly within the bacterial cell with co-enzyme A (CoA) through in vivo transfer of the N -thio group to produce an alkyl-CoA mixed disulfide species, which then interferes with fatty acid biosynthesis. Our studies on coenzyme A disulfide reductase show that the CoA thiol redox buffer is not perturbed by these compounds; however, the lactams appear to act as prodrugs. The experimental evidence that these β-lactams inhibit fatty acid biosynthesis in bacteria, and the elucidation of coenzyme A as a primary cellular target, offers opportunities for the discovery of other small organic compounds that can be developed as therapeutics for MRSA and anthrax infections.