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Targeting evolutionarily acquired insertion sequences in Candida species, for development of antifungal drugs

Award Number: R21AI169276
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting evolutionarily acquired insertion sequences in Candida species, for development of antifungal drugs - Abstract Candida albicans causes half of all invasive fungal infections in humans. Its success as a pathogen is due to its ability to adapt and thrive in various microenvironments in the host. Using a forward genetics screen, we identified an uncharacterized gene NDU1 whose loss caused C. albicans to lose viability on alternative carbon sources and made the organism completely avirulent in vivo. We found that Candida-Ndu1 protein possesses three evolutionarily acquired stretches of amino acid inserts (~64 amino acids), absent from all other eukaryotes including humans. We reported for the first time that ~17% of the Candida proteome possess “additional” sets of evolutionarily acquired amino-acid inserts, that are absent from all non-CTG clade eukaryotes, including humans. The role of insert regions in C. albicans proteome remains to be unraveled. We have shown that the Ndu1 insertion sequences are vital and required for Ndu1’s activity. In aim 1, the mechanistic contribution of Ndu1 inserts will be investigated by protein biochemistry studies. The role of insert regions in other Candida proteins will also be evaluated , to understand if inserts are universally important for function. Considering Ndu1 is important for growth and virulence in vivo, we targeted Ndu1 and its insert regions for development of antifungal molecules. We identified a repurposed FDA approved drug niclosamide (NCL), and developed Eudragit EPO nanoparticle formulations of this molecule to enhance its solubility and bioavailability. NCL nanoparticles (NCL-EPO-NP) could prevent growth of Candida in alternative carbon sources, penetrate and dismantle mature biofilms in vitro, and eradicate it in vivo in biofilm models of mucosal candidiasis. The activity of NCL-NP was 6-10 fold higher than the generic drug alone. In Aim 2, we further characterize and evaluate NCL-EPO-NP for their pharmacokinetics and oral biodistribution, toxicity profiles and in vivo efficacy in an oral regimen for treatment of oral candidiasis, as standalone or adjunct therapy with other antifungal drugs.


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 = -$16,873 )
2025	2024	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/29/2025	NON-COMPETING CONTINUATION	-$16,873
														Subtotal = -$16,873

Issue Date FY: 2024 ( Subtotal = $256,025 )
2024	2024	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	10/25/2023	NON-COMPETING CONTINUATION	$230,423
2024	2024	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	2	5/13/2024	NON-COMPETING CONTINUATION	$25,602
														Subtotal = $256,025

Issue Date FY: 2023 ( Subtotal = $201,875 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	11/18/2022	NEW	$201,875
														Subtotal = $201,875

Grand Total All Awards = $441,027

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Targeting evolutionarily acquired insertion sequences in Candida species, for development of antifungal drugs

Award Number: R21AI169276

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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