Tuesday, September 16, 2025 9/16/2025

Genetic determinants of bacterial-drug synergy against Candida

Award Number: R15AI169393
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/18/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Genetic determinants of bacterial-drug synergy against Candida - Opportunistic infections in hospitalized patients remain an important unsolved clinical problem, leading to an estimated 230,000 annual deaths in the US and Europe. Two of the most important opportunistic pathogens are the fungus Candida albicans and the gram-negative bacterium Pseudomonas aeruginosa. They are frequently co-isolated in ventilated patients and in cystic fibrosis, where co-association is linked to exacerbated disease. Drug treatment of these two opportunistic infections is often problematic, and we hypothesize that some of these failures are due to the impact of microbe-microbe and microbe-immune interactions during co- infection. The proposed research seeks to address this major gap in our understanding to define whether the complexity of co-infection demands a different view of therapeutic strategy. Our overall goal is to understand how Pseudomonas-Candida interactions affect virulence and therapeutic success. We recently found that the antifungal drug fluconazole (FLC) is much more effective and fungicidal against C. albicans in the presence of P. aeruginosa, both in vitro and in vivo. In this proposal, our driving hypothesis is that specific bacterial virulence factors block fungal tolerance to FLC. We hypothesize that iron starvation and calcineurin signaling are two key elements in this synergy, based on our preliminary data as well as published work connecting iron homeostasis and calcineurin to drug tolerance. Leveraging the power of intravital imaging in zebrafish together with microbial genomics will enable our genetic analyses of bacteria and fungi in the context of treatment and infection. We propose to uncover novel bacterial and fungal contributors to P. aeruginosa-FLC synergy against C. albicans through a complementary candidate gene/unbiased screening strategy in vitro (Aim 1). We will then utilize longitudinal intravital imaging of fungi, bacteria, and innate immune cells in the transparent zebrafish to test the relevance of these mechanisms and the innate immune contributions to fungal therapy during co-infection in the vertebrate host (Aim 2). The findings from these proposed studies will yield a network of bacterial and fungal pathways that operate in vivo to regulate drug susceptibility. This proposal has the potential to open up a new front in our study of how communication between bacteria and fungi during infection regulates drug susceptibility. While this is a basic science research proposal that will reveal new cross-kingdom interactions during infection, the focus on antifungal treatment also has significant potential for informing future translational research.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Allergy and Infectious Diseases Research	000	1	8/19/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $435,110 )
2023	2023	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL RM 422	ORONO	ME	04469	PENOBSCOT	USA	Allergy and Infectious Diseases Research	000	1	11/18/2022	NEW	$435,110
														Subtotal = $435,110

Grand Total All Awards = $435,110

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Genetic determinants of bacterial-drug synergy against Candida

Award Number: R15AI169393

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/18/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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