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Identifying Synergistic Rifabutin-Containing Combinations Against A. baumannii

Award Number: R01AI179046
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: 03/11/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2030

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Identifying Synergistic Rifabutin-Containing Combinations Against A. baumannii - PROJECT SUMMARY/ABSTRACT We have recently identified that rifabutin (RBT) is hyper potent against A. baumannii and we have described this unique mechanism of action. We have characterized the mechanism for the hyperactivity and found that RBT hijacks the A. baumannii iron transport protein FhuE, resulting in a Trojan horse-like, active accumulation in the bacterial cell. However, FhuE expression is suppressed in the presence of rich media, containing a high amount of free iron, and is expressed only in nutrient depleted conditions (e.g., RPMI-1640 media and in vivo), explaining why RBT has been previously overlooked. There is clinical interest in the translation of RBT for A. baumannii therapy and BV100 (RBT IV formulation) is currently being studied in a phase I clinical trial (NCT04636983) and phase II clinical trial (NCT05685615). However, significant barriers remain for the adoption of RBT as a treatment for A. baumanniii infections. The goal of this proposal is to further support clinical translation through the rigorous testing of a broad panel of clinical isolates, to develop a preclinical mouse model to model key RBT humanized pharmacokinetics (PK) parameters to support defining MIC breakpoints, and to establish a high-throughput RBT susceptibility testing protocol with low iron media that can be adopted by clinical labs according to CLSI standards. Specific Aim 1: Develop and validate a RBT susceptibility testing method according to CLSI standards. A) Head-to-head comparison of disc diffusion, or iron-depleted MHII and RPMI-1640 broth microdilution for RBT susceptibility testing across independent testing sites. B) Validate quality control (QC) strains for RBT susceptibility testing across independent testing sites. C) Using our optimized testing method, determine MICs for 250 international A. baumannii clinical isolates. Specific Aim 2: Characterize RBT-antibiotic drug combinations in vitro to identify synergy and antagonism. A) Determine RBT-antibiotic interactions for antibiotics using a checkerboard assay. B) Determine bacterial killing and frequency of resistance emergence using a hollow fiber infection model. Specific Aim 3: Characterize RBT-containing therapeutic combinations in murine blood and lung infection models. A) Determine if RBT-containing antibiotic combinations show in vivo synergy when measuring CFUs as an endpoint in murine blood and lung infection models. B) Determine if RBT-containing antibiotic combinations show in vivo synergy when measuring time to moribund condition as an endpoint in murine blood and lung infection models.


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 = $681,522 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	2	1/22/2026	NON-COMPETING CONTINUATION	$681,522
2026	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	12/24/2025	OTHER REVISION	$0
														Subtotal = $681,522

Issue Date FY: 2025 ( Subtotal = -$309,133 )
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	4/18/2025	TERMINATION	$0
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	6/10/2025	TERMINATION	-$309,133
														Subtotal = -$309,133

Issue Date FY: 2024 ( Subtotal = $688,572 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	5/30/2024	NEW	$67,210
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	3/11/2024	NEW	$621,362
														Subtotal = $688,572

Grand Total All Awards = $1,060,961

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Identifying Synergistic Rifabutin-Containing Combinations Against A. baumannii

Award Number: R01AI179046

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: 03/11/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2030

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