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An Inhibitor Class That Abrogates Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus

Award Number: R01AI195933
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: 05/22/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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An Inhibitor Class That Abrogates Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus - Project Summary Staphylococcus aureus, designated as a serious public health threat, causes >323,000 hospitalizations and kills >10,000 individuals annually in the United States alone. A number of antibiotic-resistant variants of S. aureus—the variants referred to as methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA)—are among the most serious bacterial pathogens. This grant application targets this nefarious pathogen for intervention by small molecules. We disclose that the integral-membrane protein BlaR is a suitable target for inhibition by small molecules, whereupon the b-lactam- resistant bacterium becomes sensitive to b-lactam antibiotics. The BlaR protein is a b-lactam sensor/signal transducer protein that serves as a sentinel for detection of b-lactam antibiotics in the growth medium. Once the sensing of the antibiotic takes place, signal transduction across the membrane initiates cytoplasmic events that culminate in derepression of the antibiotic-resistance gene, resulting in full-blown resistance response to b-lactam antibiotics. We document for the first time that a class of designer boronates covalently modify the sensor domain of BlaR. Compound 15, an advance lead, potentiates by 16- to 4096-fold the activity of oxacillin and of meropenem against a broad range of strains of MRSA (and variants) of distinct clonal origins, lowering the minimal-inhibitory concentrations (MICs) of the antibiotics to below their clinical breakpoint MICs. The combination of 15 with oxacillin or meropenem shows efficacy in MRSA-infected mice, validating the strategy. The grant application proposes to optimize the boron-based adjuvants imparted it with drug-like attributes both as a mechanistic tool in studies of S. aureus as well as a potential therapeutic agent (Specific Aims 1 and 2). Furthermore, we will explore how resistance to these agents could emerge (Specific 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 = $748,964 )
2026	2026	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Allergy and Infectious Diseases Research	000	1	5/26/2026	NEW	$748,964
														Subtotal = $748,964

Grand Total All Awards = $748,964

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An Inhibitor Class That Abrogates Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus

Award Number: R01AI195933

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: 05/22/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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