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Pneumocystis S-adenosylmethionine transport: a potential drug target

Oscar Perez-Leal1, Camilo Moncada, Allen B Clarkson

  • 1Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.

American Journal of Respiratory Cell and Molecular Biology
|June 7, 2011
PubMed

Insights

Pneumocystis pneumonia (PCP) drug discovery is advanced by identifying PcPET8, a novel S-adenosylmethionine transporter. This finding offers a new target for developing treatments against this opportunistic fungal infection.

Area of Science:

  • Medical Mycology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pneumocystis pneumonia (PCP) poses a severe threat to immunocompromised individuals, with limited therapeutic options.
  • Pneumocystis fungi rely on host S-adenosylmethionine (AdoMet) due to their inability to synthesize it, leading to host AdoMet depletion.
  • Targeting AdoMet uptake presents a promising strategy for novel anti-Pneumocystis therapies.

Purpose of the Study:

  • To identify and characterize novel genes involved in AdoMet transport in Pneumocystis.
  • To validate the role of AdoMet transport as a potential drug target for PCP treatment.
  • To develop a yeast-based screening system for anti-Pneumocystis drug discovery.

Main Methods:

  • Bioinformatic analysis to identify Pneumocystis genes homologous to known AdoMet transporters.
  • Functional expression of candidate genes in Saccharomyces cerevisiae to assess mitochondrial localization and complementation.
  • In vitro assays using sinefungin to evaluate AdoMet uptake inhibition and assess growth inhibition.

Main Results:

  • Discovery and characterization of PcPET8, a Pneumocystis gene encoding a mitochondrial AdoMet transporter.
  • Successful localization of PcPET8 to mitochondria in yeast and complementation of yeast lacking native AdoMet transporter.
  • Sinefungin effectively blocked Pneumocystis AdoMet uptake and inhibited fungal growth in culture.

Conclusions:

  • PcPET8 is a functional mitochondrial AdoMet transporter critical for Pneumocystis.
  • AdoMet transport is a validated drug target for Pneumocystis infections.
  • The engineered yeast expressing PcPET8 serves as a valuable surrogate model for screening anti-PCP drug candidates.

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