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Identification of Putative Non-Substrate-Based XT-I Inhibitors by Natural Product Library Screening.

ABSTRACT: Fibroproliferative diseases are characterized by excessive accumulation of extracellular matrix (ECM) components leading to organ dysfunction. This process is characterized by an increase in myofibroblast content and enzyme activity of xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan (PG) biosynthesis. Therefore, the inhibition of XT-I could be a promising treatment for fibrosis. We used a natural product-inspired compound library to identify non-substrate-based inhibitors of human XT-I by UPLC-MS/MS. We combined this cell-free approach with virtual and molecular biological analyses to confirm and prioritize the inhibitory potential of the compounds identified. The characterization for compound potency in TGF-?1-driven XYLT1 transcription regulation in primary dermal human fibroblasts (key cells in ECM remodeling) was addressed by gene expression analysis. Consequently, we identified amphotericin B and celastrol as new non-substrate-based XT-I protein inhibitors. Their XT-I inhibitory effects were mediated by an uncompetitive or a competitive inhibition mode, respectively. Both compounds reduced the cellular XYLT1 expression level and XT-I activity. We showed that these cellular inhibitor-mediated changes involve the TGF-? and microRNA-21 signaling pathway. The results of our study provide a strong rationale for the further optimization and future usage of the XT-I inhibitors identified as promising therapeutic agents of fibroproliferative diseases.

SUBMITTER: Ly TD

PROVIDER: S-EPMC7589200 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Identification of Putative Non-Substrate-Based XT-I Inhibitors by Natural Product Library Screening.

Ly Thanh-Diep TD Kleine Anika A Fischer Bastian B Schmidt Vanessa V Hendig Doris D Kuhn Joachim J Knabbe Cornelius C Faust Isabel I

Biomolecules 20201021 10

Fibroproliferative diseases are characterized by excessive accumulation of extracellular matrix (ECM) components leading to organ dysfunction. This process is characterized by an increase in myofibroblast content and enzyme activity of xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan (PG) biosynthesis. Therefore, the inhibition of XT-I could be a promising treatment for fibrosis. We used a natural product-inspired compound library to identify non-substrate-based inhibitors of huma ...[more]

PMID: 33096778

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Project description:Health organizations worldwide have warned that we are on the cusp of a "post-antibiotic era," necessitating new approaches to combat antibiotic resistant infections. One such approach is the development of antibiotic adjuvants, which have little or no inherent antibiotic activity at their active concentrations but instead potentiate the activity of antibiotics against antibiotic-resistant bacteria. Recently, we demonstrated that meridianin D, a natural product originally reported to have activity against Staphylococcus aureus and Mycobacterium tuberculosis, possesses the ability to reverse colistin resistance in colistin resistant bacteria. As most natural product screens typically involve screening for only certain activities (anticancer, antiviral, and antimicrobial are typical), we posited that the meridianin D discovery was not unique and there are potentially many natural products that have adjuvant activity. To explore this, the National Cancer Institute (NCI) Natural Product Library Set IV was screened for adjuvant activity using four classes of antibiotics (β-lactams, aminoglycosides, macrolides, and polymyxins) against three bacterial pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae). Sixteen compounds suppressed β-lactam resistance in MRSA, five of which effected a 16-fold reduction in the oxacillin minimum inhibitory concentration (MIC). Two natural products effectively suppressed aminoglycoside resistance in both of the Gram-negative species tested, and no hits were observed with macrolides. In contrast, a larger number of natural product adjuvants were identified when screening against colistin-resistant strains of A. baumannii and K. pneumoniae. Nine compounds reduced the colistin MIC to its breakpoint or lower (up to a 1024-fold reduction). Clorobiocin, novobiocin, and prodigiosin were most effective, reducing the colistin MIC in K. pneumoniae strain B9 to 2 μg/mL at concentrations as low as 0.625, 2.5, and 1.25 μM, respectively. Restored sensitivity to colistin with these compounds does not appear to coincide with known mechanisms of colistin resistance.

Dataset Information

Identification of Putative Non-Substrate-Based XT-I Inhibitors by Natural Product Library Screening.

Publications

Identification of Putative Non-Substrate-Based XT-I Inhibitors by Natural Product Library Screening.

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