# Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis

> **NIH NIH R01** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2021 · $393,191

## Abstract

Abstract
A single species Candida albicans, causes half of all invasive fungal infections in humans. The ability of C.
albicans to switch reversibly between yeast and hyphe is a major virulence trait that helps it disseminate into
the bloodstream (yeast) and invade target organs (filaments). Yeast to hyphae morphogenesis has been
extensively studied and its regulation well understood. To the contrary, little is known about the reverse
process: hyphae to yeast growth. C. albicans hyphae produce yeast cells from their lateral septal regions,
coined as “lateral yeasts”. These lateral yeasts are always found with hyphae at the site of active infection,
are the major cells that re- enter the bloodstream and establish distal foci of infection. In fact, lateral yeast
cells released from the hyphal layers of biofilm-contaminated catheters have direct access into the
bloodstream. We identified the first regulator of hyphae-to-lateral yeast growth, PES1 and have shown that
blocking the process (by depleting PES1 in vivo) can abrogate disseminated candidiasis as well as biofilm-
associated candidemia. Nothing is known on the regulatory aspects pf PES1. Our preliminary studies show
that phosphorylation of Pes1 by Ras-PKA inhibits lateral yeast growth while its dephosphorylation by a Ras-
linked phosphatase Yvh1 activates lateral yeast emergence from hyphae and induces biofilm dispersal. Using
PES1 as a target for identifying small molecule inhibitors of lateral yeast growth, identified alexidine
dihydrochloride that directly inhibited both Pes1 and Yvh1 and protected mice from biofilm-associated
disseminated candidiasis. Here, using protein biochemistry assays, we propose to delineate how signaling
through Ras-PKA regulates Pes1. We will identify other cognate regulators that interact with Pes1 to control
lateral yeast growth, and use this information to discover novel compounds that can interrupt hyphae to lateral
yeast growth and disseminated candidiasis. Ultimately, better outcomes for patients with indwelling medical
devices is the goal of this application.

## Key facts

- **NIH application ID:** 10215503
- **Project number:** 5R01AI141794-03
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** PRIYA UPPULURI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,191
- **Award type:** 5
- **Project period:** 2019-08-09 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215503

## Citation

> US National Institutes of Health, RePORTER application 10215503, Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis (5R01AI141794-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215503. Licensed CC0.

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