NIH grant: Copper scavenging mechanisms in fungal pathogens (1R35GM165814-01)

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NIH grant 1R35GM165814-01: Copper scavenging mechanisms in fungal pathogens
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Ryan Loren Peterson. Award: $399248.
Start: 2026-08-01T00:00:00.
Project Summary
The overarching goal of this R35 MIRA-ESI proposal is to enhance our fundamental understanding of the
strategies employed by fungal pathogens to scavenge essential copper (Cu) micronutrients. It is crucial for
fungal pathogens to outcompete the metal-sequestering strategies of the host's innate immune response in
order to establish and proliferate efficiently on their infected animal host. The long-term research goal of the
Peterson group at TX State University is to develop Pseudogymnoascus destructans (Pd) as a model system
to understand the mechanisms that opportunistic fungal pathogens found in the environment or soil can adapt
to and thrive in new ecological niches. The three distinct projects described in this proposal will address gaps
in our understanding of the Cu-scavenging mechanisms that fungi employ using secreted metallophore small
molecules, and protein homologs to lytic polysaccharide monooxygenases (LPMOs) or Cryptococcus
neoformans BIM1 (CnBIM1). This proposal will use a combination of biochemical, biophysical, and cell biology
approaches to interrogate these extracellular metal-binding strategies. Project 1 will focus on characterizing the
metal-binding properties and biosynthetic pathway of a metallophore secreted by Pd under Cu-limited growth
conditions. We hypothesize that this metallophore is a member of the opine-based metallophores (OpM) that
are biosynthesized by genes encoded in the Copper Responsive Cluster (CRC) recently reported by our
laboratory. To date, OpMs have not been described in fungal systems and are thought to be exclusive to
bacteria. The proposed experiments employ an unbiased approach to identify and characterize the metal-
binding properties of the natively produced metallophore. Biochemical and biophysical characterization
experiments of recombinantly expressed CRC enzymes are proposed to address unanswered questions
regarding Pd OpM biosynthesis and enzymology. Project 2 will focus on describing Pd's CRC and Cu-cell
biology. We will generate targeted CRC deletion strains to interrogate aspects of CRC gene function and
trafficking mechanistic details. Additionally, we will generate knockout strains of the two putative Pd Cu-sensing
transcription factors, with homology to ACE1/MAC1, and describe their role in CRC gene regulation as well as
the global Pd Cu-stress response. These experiments will make significant strides in understanding the
mechanisms for maintaining Cu-homeostasis in non-model fungal species. In Project 3, we will investigate a
conundrum regarding extracellular Cu-trafficking involving fungal species that contain multiple homologs to
CnBIM1. Using the three unique and transcriptionally active BIM1-like proteins (BLPs) found in Pd, we will
investigate their roles in scavenging trace copper. Proposed experiments will investigate their extracellular
spatial distribution and remodeling during morphological changes, and in response to environmental stress.
Collectively, the experiments in this proposal will further our understanding of methods that fungi use to adapt
and capture essential Cu-micronutrients.

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