Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics.
Covering: up to 2014. Dithiolopyrrolone (DTP) group antibiotics were first isolated in the early half of the 20th century, but only recently has research been reawakened by insights gained from the synthesis and biosynthesis of this structurally intriguing class of molecules. DTPs are characterized by an electronically unique bicyclic structure, which contains a compact disulfide bridge between two ene-thiols. Points of diversity within the compound class occur outside of the bicyclic core, at the two amide nitrogens. Such modifications distinguish three of the most well studied members of the class, holomycin, thiolutin, and aureothricin; the DTP core has also more recently been identified in the marine antibiotic thiomarinol, in which it is linked to a marinolic acid moiety, analog of the FDA-approved topical antibiotic Bactroban® (GlaxoSmithKline). Dithiolopyrrolones exhibit relatively broad-spectrum antibiotic activity against many Gram-positive and Gram-negative bacteria, as well as strains of Mycobacterium tuberculosis. Additionally, they have been shown to exhibit potent and selective anti-cancer activity. Despite this promising profile, there is still much unknown about the mechanisms of action for DTPs. Early reports suggested that they inhibit yeast growth at the level of transcription and that this effect is largely responsible for their distinctive microbial static properties; a similar mechanism is supported in bacteria. Elucidation of biosynthetic pathways for holomycin in Streptomyces clavuligerus and Yersinia ruckeri and thiomarinol in Alteromonas rava sp. nov. SANK 73390, have contributed evidence suggesting that multiple mechanisms may be operative in the activity of these compounds. This review will comprehensively cover the history and development of dithiolopyrrolones with particular emphasis on the biosynthesis, synthesis, biological activity and mechanism of action.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. boli@email.unc.edu.
Bo
B
Li
Walter J
WJ
Wever
Christopher T
CT
Walsh
Albert A
AA
Bowers
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001688:Biological Products; D004220:Disulfides; D011758:Pyrroles; D013438:Sulfhydryl Compounds