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A novel link between calcineurin, amino acid permease, and protein kinase A in virulence in Mucor

Award Number: R01AI182221
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: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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A novel link between calcineurin, amino acid permease, and protein kinase A in virulence in Mucor - Summary Mucormycosis, which is caused by Mucorales fungi, is a life-threatening condition that poses a challenge to immunocompromised patients. As the susceptible cohort increases, the incidence of mucormycosis is rising. Mucormycosis has an unacceptably high mortality rate of more than 90% in disseminated infections and 50% overall in all cases. To make matters even worse, a number of reports concern the high level of intrinsic antifungal resistance in Mucorales. Therefore, there is an urgent need for the development of new antifungals to overcome lethal fungal infections. One very well-known virulence factor in fungi is calcineurin, a serine/threonine phosphatase, which is required for the invasive hyphal growth in the model Mucorales Mucor circinelloides (denote Mucor). This attribute of the phosphatase makes a highly attractive target of antifungal drugs. However, calcineurin is highly conserved in fungi and humans, which in practical terms has translated into our inability (despite major efforts by multiple groups of investigators over the years) to directly use pharmacological inhibition of calcineurin as an antifungal strategy. Fungal specific downstream of calcineurin that is absent in mammalian cells will potentially solve the conundrum and open a brand-new avenue for the development of novel antifungal drugs. During preliminary studies, we discovered that, in Mucor, 1) mutations in an amino acid permease gene results in resistance to calcineurin inhibitors such as FK506, 2) the resistance is caused by an elevated activity of protein kinase A (PKA), and 3) the amino acid permease positively regulates the activity of PKA. These observations have never been reported in any fungal systems and will lead a completely different direction to study calcineurin as a target for drugs. Based on this observation, our hypothesis in this proposal is that the resistance mechanism to calcineurin inhibitors via the genetic link between calcineurin, amino acid permease, and PKA is conserved in pan-fungal systems. Three specific aims include identification of a key transcription factor(s) regulated by calcineurin in the regulation of the amino acid permease BycA expression (Aim 1), elucidation of the roles of BycA in virulence (Aim 2), and demonstration of the link between BycA and PKA (Aim 3).


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: 2026 ( Subtotal = $576,767 )
2026	2026	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Allergy and Infectious Diseases Research	000	2	1/15/2026	NON-COMPETING CONTINUATION	$576,767
														Subtotal = $576,767

Issue Date FY: 2025 ( Subtotal = $558,747 )
2025	2025	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Allergy and Infectious Diseases Research	000	1	1/30/2025	NEW	$558,747
														Subtotal = $558,747

Grand Total All Awards = $1,135,514

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A novel link between calcineurin, amino acid permease, and protein kinase A in virulence in Mucor

Award Number: R01AI182221

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: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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