A Nonredundant Phosphopantetheinyl Transferase, PptA, Is a Novel Antifungal Target That Directs Secondary Metabolite, Siderophore, and Lysine Biosynthesis in Aspergillus fumigatus and Is Critical for Pathogenicity

Research output: Contribution to journalArticle

  • External authors:
  • Anna Johns
  • Daniel H. Scharf
  • Fabio Gsaller
  • Hella Schmidt
  • Thorsten Heinekamp
  • Maria Strassburger
  • Jason D. Oliver
  • Mike Birch
  • Nicola Beckmann
  • Katharine S Dobb
  • Bharatkumar Rash
  • Axel A Brakhage

Abstract

Secondary metabolites are key mediators of virulence for many pathogens.
Aspergillus fumigatus produces a vast array of these bioactive molecules, the
biosynthesis of which is catalyzed by nonribosomal peptide synthetases (NRPSs) or
polyketide synthases (PKSs). Both NRPSs and PKSs harbor carrier domains that are
primed for acceptance of secondary metabolic building blocks by a phosphopantetheinyl
transferase (P-pant). The A. fumigatus P-pant PptA has been shown to prime the
putative NRPS Pes1 in vitro and has an independent role in lysine biosynthesis; however,
its role in global secondary metabolism and its impact on virulence has not
been described. Here, we demonstrate that PptA has a nonredundant role in the
generation of the vast majority of detectable secondary metabolites in A. fumigatus,
including the immunomodulator gliotoxin, the siderophores triacetylfusarinine C
(TAFC) and ferricrocin (FC), and dihydroxy naphthalene (DHN)-melanin. We show
that both the lysine and iron requirements of a pptA null strain exceed those freely
available in mammalian tissues and that loss of PptA renders A. fumigatus avirulent
in both insect and murine infection models. Since PptA lacks similarity to its mammalian
orthologue, we assert that the combined role of this enzyme in both primary
and secondary metabolism, encompassing multiple virulence determinants makes it
a very promising antifungal drug target candidate. We further exemplify this point
with a high-throughput fluorescence polarization assay that we developed to identify
chemical inhibitors of PptA function that have antifungal activity

Bibliographical metadata

Original languageEnglish
Pages (from-to)e01504-16
Number of pages13
JournalmBio
Volume8
Issue number4
Early online date18 Jul 2017
DOIs
Publication statusPublished - 2017

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