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Tofacitinib Analogs as Oxacillin Potentiators against MRSA

Award Number: F31AI169961
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 10/14/2024

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Tofacitinib Analogs as Oxacillin Potentiators against MRSA - Project Summary Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) infections are among the most frequently occurring and dangerous antibiotic-resistant public health threat. Clinical resistance to all front-line MRSA antibiotics (i.e. vancomycin, linezolid, daptomycin, and ceftaroline) has been observed, further exacerbating this threat and highlighting the urgent need for new strategies to overcome drug resistance in S. aureus. In recent years, there has been increased interest in targeting signal transduction systems for development as antimicrobials and anti-virulence agents. Targeting bacterial signal transduction is attractive because these systems are essential for many cellular processes in prokaryotes, and signal transduction pathways have been extensively studied in eukaryotic systems, as evidenced by the availability of chemical libraries containing small molecule probes with kinase inhibitor-like properties. With this strategy in mind, we screened a focused set of kinase inhibitors and identified tofacitinib, an antirheumatic Janus kinase inhibitor, as a potential chemistry starting point for the discovery of beta-lactam potentiators against MRSA. Several pyrrolopyridin-4- amine (P4A) analogs of tofacitinib were synthesized, which led to the discovery of potent analogs with the ability to re-sensitize oxacillin (OXA; a beta-lactam antibiotic) against MRSA. Preliminary pull-down proteomic experiments have identified PurM, SrrB, and PknB as putative targets, studies that have been complemented by gene knockout experiments. Therefore, the main scientific objective of this proposal is to confirm P4A engagement of putative targets using biophysical and biochemical techniques and to establish the therapeutic potential of tofacitinib analogs as anti-virulence agents and OXA potentiators against MRSA. In Aim 1, I will evaluate the binding of lead P4A compounds to putative targets, demonstrate inhibition of S. aureus kinase activity and determine the extent of potential off-target effects on mammalian kinases. Biophysical assays will be developed against the putative targets through a novel target engagement assay, which will be complemented with biochemical phosphorylation and ATP/ADP conversion assays. In Aim 2, I will evaluate the clinical potential of the P4A compounds through anti-biofilm studies, pharmacological ADME profiling, and in vivo efficacy against MRSA in a mouse model. The research plan will enhance my training in areas of target identification and validation, biophysical analysis, and anti-infective microbiology, benefiting from the expertise of my co-mentors, Drs. Richard Lee and Jason Rosch, and the state-of-the-art resources at St. Jude.


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 = -$2,174 )
2026	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$2,174
														Subtotal = -$2,174

Issue Date FY: 2025 ( Subtotal = -$8,346 )
2025	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	-$8,346
														Subtotal = -$8,346

Issue Date FY: 2024 ( Subtotal = $44,974 )
2024	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	2	5/15/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$43,694
														Subtotal = $44,974

Issue Date FY: 2023 ( Subtotal = $43,694 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	002	1	3/2/2023	NEW	$942
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	1	1/19/2023	NEW	$0
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	1	1/19/2023	NEW	$42,752
														Subtotal = $43,694

Grand Total All Awards = $78,148

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Tofacitinib Analogs as Oxacillin Potentiators against MRSA

Award Number: F31AI169961

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 10/14/2024

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