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A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1.

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  • معلومة اضافية
    • المصدر:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: [London] : Nature Pub. Group
    • الموضوع:
      Aspergillus fumigatus*/drug effects ; Aspergillus fumigatus*/metabolism ; Aspergillus fumigatus*/genetics ; Antifungal Agents*/pharmacology ; Triazoles*/pharmacology ; Fungal Proteins*/metabolism ; Fungal Proteins*/genetics ; Ergosterol*/metabolism ; Ergosterol*/biosynthesis ; Hydroxymethylglutaryl CoA Reductases*/metabolism ; Hydroxymethylglutaryl CoA Reductases*/genetics; Aspergillosis/drug therapy ; Aspergillosis/microbiology ; Drug Resistance, Fungal/genetics ; Drug Resistance, Fungal/drug effects ; Gene Expression Regulation, Fungal/drug effects ; Cytochrome P-450 Enzyme System/metabolism ; Cytochrome P-450 Enzyme System/genetics ; Microbial Sensitivity Tests ; Sterol 14-Demethylase/metabolism ; Sterol 14-Demethylase/genetics ; Humans ; Mutation
    • نبذة مختصرة :
      Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.
      (© 2024. The Author(s).)
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    • Grant Information:
      P30 CA021765 United States CA NCI NIH HHS; R01 AI143197 United States AI NIAID NIH HHS; R01 AI158442 United States AI NIAID NIH HHS; U19 AI110820 United States AI NIAID NIH HHS
    • الرقم المعرف:
      0 (Antifungal Agents)
      0 (Triazoles)
      0 (Fungal Proteins)
      Z30RAY509F (Ergosterol)
      EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
      EC 1.14.14.- (cytochrome P-450 CYP51A, Aspergillus)
      9035-51-2 (Cytochrome P-450 Enzyme System)
      EC 1.14.14.154 (Sterol 14-Demethylase)
      EC 1.14.14.- (cytochrome P-450 CYP51B, Aspergillus)
    • الموضوع:
      Date Created: 20240429 Date Completed: 20240429 Latest Revision: 20240502
    • الموضوع:
      20240502
    • الرقم المعرف:
      PMC11059170
    • الرقم المعرف:
      10.1038/s41467-024-48029-2
    • الرقم المعرف:
      38684680