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Targeted development and selective delivery of small molecule antibiotics for the treatment of multidrug resistant infections caused by Gram-negative pathogens

Award Number: R15AI163474
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Targeted development and selective delivery of small molecule antibiotics for the treatment of multidrug resistant infections caused by Gram-negative pathogens - PROJECT SUMMARY While the incidence of multidrug resistant bacterial infection has increased, the field of antibiotic development has stagnated over the past half-century due to the challenges associated with developing small molecules capable of overcoming bacterial resistance mechanisms that can render entire antibiotic classes in active. Gram- negative, biofilm-forming pathogens, like Pseudomonas aeruginosa (PA) and Acinetobacter baumannii (AB), have been deemed critical priority targets by the World Health Organization due to the lack of treatment options and high mortality rates in immunocompromised individuals including children and the elderly. Most clinically approved antibiotics target three cellular processes (cell wall synthesis, protein synthesis, and nucleic acid synthesis), which are protected by resistance mechanisms, including target modification, enzyme inactivation, and increased efflux. PA and AB can further avoid antibiotic action due to their additional outer membrane (OM) and ability to form biofilms, both of which reduces antibiotic accumulation within the cell. Therefore, there is a dire need for new antibiotics that target novel cellular mechanisms and that can overcome accumulation issues in Gram-negative pathogens. Enzymes involved in bacterial oxidative phosphorylation (OxPhos) are underexplored and highly promising targets for selective antibiotic development because they are essential cellular processes, located in the inner membrane of Gram-negative bacteria, and have a limited rate of target modification mutation. This work will interrogate multiple enzyme complexes in the PA and AB OxPhos system, including ATP synthase and electron transport chain complexes for antibiotic development. The project uses a multistage approach targeting multiple aspects of OxPhos, from later stage expansion and optimization of an existing library of ATP synthase inhibitors, particularly focusing on penetration of the OM and bacterial biofilms in vivo, (Aim 1), to the development an inhibitor library and high-throughput biochemical methods to interrogate new targets in the respiration phase of OxPhos (Aim 2). This work will not only produce new and highly efficacious small molecules to treat multidrug resistant PA and AB infections, it will also lay groundwork for future strategies targeting bacterial bioenergetics that can be applied to a variety of pathogenic bacteria to generate desperately needed new antibiotics.


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 = $504,305 )
2026	2026	THE UNIVERSITY OF NORTH CAROLINA AT ASHEVILLE	1 UNIVERSITY HEIGHTS	ASHEVILLE	NC	28804	BUNCOMBE	USA	Allergy and Infectious Diseases Research	000	2	4/9/2026	COMPETING CONTINUATION	$504,305
														Subtotal = $504,305

Issue Date FY: 2025 ( Subtotal = -$17,966 )
2025	2021	THE UNIVERSITY OF NORTH CAROLINA AT ASHEVILLE	1 UNIVERSITY HEIGHTS	ASHEVILLE	NC	28804	BUNCOMBE	USA	Allergy and Infectious Diseases Research	000	1	9/16/2025	NEW	-$17,966
														Subtotal = -$17,966

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	THE UNIVERSITY OF NORTH CAROLINA AT ASHEVILLE	1 UNIVERSITY HEIGHTS	ASHEVILLE	NC	28804	BUNCOMBE	USA	Allergy and Infectious Diseases Research	000	1	5/16/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $384,353 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT ASHEVILLE, THE	ONE UNIVERSITY HEIGHTS	ASHEVILLE	NC	28804	BUNCOMBE	USA	Allergy and Infectious Diseases Research	000	1	7/1/2021	NEW	$384,353
														Subtotal = $384,353

Grand Total All Awards = $870,692

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Targeted development and selective delivery of small molecule antibiotics for the treatment of multidrug resistant infections caused by Gram-negative pathogens

Award Number: R15AI163474

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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