Dataset Information

Pyrancoumarin derivative LP4C targeting of pyrimidine de novo synthesis pathway inhibits MRSA biofilm and virulence.

ABSTRACT: Staphylococcus aureus poses a serious public health threat because of its multidrug resistance and biofilm formation ability. Hence, developing novel anti-biofilm agents and finding targets are needed to mitigate the proliferation of drug-resistant pathogens. In our previous study, we showed that the pyrancoumarin derivative 2-amino-4-(2,6-dichlorophenyl)-3-cyano-5-oxo-4H, 5H- pyrano [3,2c] chromene (LP4C) can destroy the biofilm of methicillin-resistant S. aureus (MRSA) in vitro and in vivo. Here, we further explored the possible mechanism of LP4C as a potential anti-biofilm drug. We found that LP4C inhibits the expression of enzymes involved in the de novo pyrimidine pathway and attenuates the virulence of MRSA USA300 strain without affecting the agr or luxS quorum sensing system. The molecular docking results indicated that LP4C forms interactions with the key amino acid residues of pyrR protein, which functions as the important regulator of bacterial pyrimidine synthesis. These findings reveal that pyrancoumarin derivative LP4C inhibits MRSA biofilm formation and targeting pyrimidine de novo synthesis pathway.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9486200 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Pyrancoumarin derivative LP4C targeting of pyrimidine de novo synthesis pathway inhibits MRSA biofilm and virulence.

Liu Yongsheng Y Su Shan S Yu Moxi M Zhai Dongshen D Hou Yachen Y Zhao Hui H Ma Xue X Jia Min M Xue Xiaoyan X Li Mingkai M

Frontiers in pharmacology 20220906

Staphylococcus aureus poses a serious public health threat because of its multidrug resistance and biofilm formation ability. Hence, developing novel anti-biofilm agents and finding targets are needed to mitigate the proliferation of drug-resistant pathogens. In our previous study, we showed that the pyrancoumarin derivative 2-amino-4-(2,6-dichlorophenyl)-3-cyano-5-oxo-4H, 5H- pyrano [3,2c] chromene (LP4C) can destroy the biofilm of methicillin-resistant S. aureus (MRSA) in vitr ...[more]

PMID: 36147327

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Project description:Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH's activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.

Dataset Information

Pyrancoumarin derivative LP4C targeting of pyrimidine de novo synthesis pathway inhibits MRSA biofilm and virulence.

Publications

Pyrancoumarin derivative LP4C targeting of pyrimidine <i>de novo</i> synthesis pathway inhibits MRSA biofilm and virulence.

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