The Abyssomicin C family as in vitro inhibitors of Mycobacterium tuberculosis

Abstract

SUMMARY The antimycobacterial efficacy of the abyssomicin C family of natural products, in addition to a key synthetic intermediate, has been investigated given their reported inhibition of Bacillus subtilis p-aminobenzoate biosynthesis. The naturally occurring (−)-abyssomicin C and its atropisomer were found to exhibit low micromolar growth inhibition against the relatively fast-growing and non-virulent Mycobacterium smegmatis and the vaccine strain Mycobacterium bovis BCG, while their antipodes were slightly less active. (−)-Abyssomicin C and its atropisomer were particularly efficacious against Mycobacterium tuberculosis H37Rv, exhibiting MIC values of 3.6 and 7.2 μM, respectively. More specifically, (−)-abyssomicin C was bactericidal. This complex natural product and its analogs, thus, hold promise as chemical tools in the study of M. tuberculosis metabolism.

Recent advances in the field of bioactive tetronates

“…This subtle conformational isomerism was observed in independent studies by chemical synthesis and by analysis of the fermentation broth of Verrucosispora. 84,85 Careful examination of the isolation procedure conrmed that the main compound present in the natural extract is indeed atrop-abyssomicin C, which undergoes acid-catalyzed epimerization to abyssomicin C. 85,86 Subsequent investigations of the activity of total syntheses intermediates further showed that both acylation and benzylation at the C11-hydroxyl group of abyssomicin C can be tolerated while antibiotic activity is retained or even increased. 85,87 A recent synthetic study reported cytotoxic activity of abyssomicin C against tumor and healthy cells, which could be expected from the structure given the toxicity of many Michael acceptors.…”

Design and synthesis of molecular scaffolds with anti-infective activity

“…Not only did the biomimetic synthesis featuring the Diels–Alder reaction help elucidate the biosynthesis pathway in vivo , 39 it also provided additional abyssomicin-like compounds (such as stereoisomers and advanced intermediates) for biological evaluation. 40 Chemical modifications to the enone moiety have helped confirm its role as an electrophile for the covalent modification of enzymes, with Cys-236 of ADC synthase being validated as an active nucleophilic partner. 41 This insight provides yet another example of the utility of chemical synthesis.…”

Abyssomicins from the South China Sea Deep‐Sea Sediment Verrucosispora sp.: Natural Thioether Michael Addition Adducts as Antitubercular Prodrugs

“…(Ank 210). Ongoing interest in the synthesis, biosynthesis, and pharmacology of the abyssomicins has been fuelled by the observation that abyssomicin C (5), an inhibitor of p-aminobenzoic acid (p-ABA) biosynthesis (a putative molecular target for nextgeneration antibiotics), [6] exhibits promising anti-methicillinresistant Staphylococcus aureus (MRSA) [2b] and antitubercular [7] activities. HRESI-MS measurements on abyssomicin J (1) revealed an adduct ion ([M + Na] + ) consistent with a molecular formula of C 38 H 46 O 12 S (Dmmu + 0.4).…”

“…Among the known abyssomicins, only the atropisomers 5 and 8 have been attributed anti-TB properties-against the fast growing nonpathogenic M. smegmatis, the TB surrogate BCG, and M. tuberculosis (H37Rv) [7] -and thus emphasized the critical structure-activity importance of the Michael acceptor enone moiety. [2a] Given this history, we were initially surprised to discover that, along with 5, the thioether 1 was the principle anti-TB agent in Verrucosispora sp.…”