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Precursor-Directed Generation of Indolocarbazoles with Topoisomerase II? Inhibitory Activity.

ABSTRACT: One new indolocarbazole, 3-hydroxy-K252d (3), together with the recently reported 3-hydroxyholyrine A (1) and 3'-N-acetyl-3-hydroxyholyrine A (2), were obtained by feeding a culture of the marine-derived Streptomyces strain OUCMDZ-3118 with 5-hydroxy-l-tryptophan. Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 potently induced apoptosis of gastric cancer cells by inhibiting topoisomerase II? enzyme activity and reducing the expression of antiapoptosis protein level. Compound 3 displayed moderate cytotoxicity against the A549 and MCF-7 cell lines with IC50 values of 1.2 ± 0.05 ?M, 1.6 ± 0.09 ?M, respectively.

SUBMITTER: Wang C

PROVIDER: S-EPMC5983299 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Precursor-Directed Generation of Indolocarbazoles with Topoisomerase IIα Inhibitory Activity.

Wang Cong C Monger Adeep A Wang Liping L Fu Peng P Piyachaturawat Pawinee P Chairoungdua Arthit A Zhu Weiming W

Marine drugs 20180517 5

One new indolocarbazole, 3-hydroxy-K252d (3), together with the recently reported 3-hydroxyholyrine A (1) and 3'-N-acetyl-3-hydroxyholyrine A (2), were obtained by feeding a culture of the marine-derived Streptomyces strain OUCMDZ-3118 with 5-hydroxy-l-tryptophan. Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 potently induced apoptosis of gastric cancer cells by inhibiting topoisomerase IIα enzyme activity and reduci ...[more]

PMID: 29772796

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Project description:Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. Clostridium difficile infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified Lactobacillus reuteri to be a promising candidate for adjunct therapy. Human-derived L. reuteri bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the pocR gene locus were potent reuterin producers, with L. reuteri 17938 inhibiting C. difficile growth at a level on par with the level of growth inhibition by vancomycin. Targeted pocR mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of L. reuteri with glycerol was effective against C. difficile colonization in complex human fecal microbial communities, whereas treatment with either glycerol or L. reuteri alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with L. reuteri elicited changes in the composition and function of the human microbial community that preferentially targets C. difficile outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of C. difficile, and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials.

Dataset Information

Precursor-Directed Generation of Indolocarbazoles with Topoisomerase II? Inhibitory Activity.

Publications

Precursor-Directed Generation of Indolocarbazoles with Topoisomerase IIα Inhibitory Activity.

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