Discoveries from the Abyss: The Abyssomicins and Their Total Synthesis

Abstract

Abyssomicin C is a recently discovered antibiotic with promising antibacterial activity, high structural complexity, and a novel mechanism of action. We give an account of our abyssomicin campaign and some of the discoveries that were borne of our total synthesis efforts, including a new Lewis acid-templated Diels-Alder reaction, the previously undescribed atrop-abyssomicin C, a facile Brønsted acid-catalyzed isomerization of abyssomicin C, and clarification of the likely biosynthetic origin of abyssomicin D.

Bi- and Tetracyclic Spirotetronates from the Coal Mine Fire Isolate Streptomyces sp. LC-6-2

“…18 Consistent with their lack of this reactive moiety, compounds 1 – 12 were inactive at or below 60 and 10 μ M in standard antimicrobial and cancer cell line cytotoxicity assays, respectively.…”

“…1,9,14,15 Abyssomicin C and the dimeric abyssomicin J display potent anti-Gram-positive bacteria activity, where abyssomicin J was noted as a putative oxidatively activated prodrug. 1,14,16–18 Spirotetronate biosynthesis also features novel stereoselective [4 + 2] cycloaddition macrocyclization reactions, as exemplified by abyssomicin, versipelostatin, and pyrroindomycin biosynthetic studies (Figure S1). 19–21 As part of an effort to explore the potential of actinomycetes associated with underground coal mine fires in Appalachia as a source for new natural products and/or biocatalysts, 22–31 herein we report the discovery of 12 new abyssomicin analogues (M–X, 1 – 12 ) as metabolites of the Lotts Creek coal fire-affliated isolate Streptomyces sp.…”

Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis

“…Out of all the abyssomicins screened for antimicrobial activity, only four natural abyssomicins (abyssomicin 2, C, J and atrop-abyssomicin C) [ 27 , 28 , 29 , 30 , 35 ] and nine synthetic derivatives were active ( Table 1 and Table 2 ) [ 24 , 31 , 39 , 40 , 41 , 42 , 51 ]. Active abyssomicins against Gram-positive bacteria, including Micrococcus luteus , Bacillus thuringiensis , Enterococcus faecalis , MRSA, and vancomycin-resistant S. aureus (VRSA) strains are abyssomicin C and its atropoisomer, 4 atrop-abyssomicin C derivatives (Benzyl ether derivative, Chloro derivative, and two diastereoisomeric methoxymethyl (MOM) ethers derivatives), atrop-O-benzyl-desmethylabyssomicin C, oxidized derivative of abyssomicin I, acetyl abyssomicin C, 3-dithiolane atrop -abyssomicin C, and dithiolane abyssomicin C, and abyssomicin 2 ( Table 1 ) [ 30 , 31 , 32 , 33 , 34 , 37 , 42 , 51 , 57 ]. Active abyssomicins against mycobacteria, including Mycobacterium smegmatis , M. bovis Bacille Calmette Guerin (BCG), and M. tuberculosis are abyssomicin C, atrop-abyssomicin C, and abyssomicin J ( Table 2 ) [ 35 , 36 ].…”

“…The emerging interest around the abyssomicin pharmacophore has been driven by the observations that abyssomicin C, isolated from Verrucosispora sp. (AB-18-032) in 2004 [ 27 , 28 , 29 ], inhibits the biosynthesis of pABA, a key cofactor required for folic acid biosynthesis, by trapping irreversibly the 4-amino-4-deoxychorismate synthase (ADCS) enzyme within the chorismate pathway through a Michael addition to a cysteine residue [ 30 , 31 , 32 , 33 ]. Abyssomicin C exhibits promising effects against methicillin resistant Staphylococcus aureus (MRSA) [ 34 ] and mycobacteria causing tuberculosis [ 27 , 35 , 36 ], validating pABA synthesis as a potential useful antifolate target.…”

“…The antibacterial activity of abyssomicins has been explored through biosynthetic evaluation, total synthesis, and pharmacological studies. Elegant synthetic routes have given access to new chemistries and the synthesis of several naturally occurring abyssomicins, as well as various novel analogues [ 12 , 26 , 31 , 32 , 33 , 34 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”