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Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms

Award Number: R01AI176537
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms - The alarming emergence of multidrug-resistant (MDR) pathogenic microorganisms worldwide and the lack of next-generation portfolios of novel antimicrobials threaten human and public health. Therefore, it is a worldwide priority to expedite the development of novel antimicrobial therapies to control MDR bacteria effectively. Natural and synthetic antimicrobial peptides (AMPs) exhibit great potential as therapeutic agents because of their unique modes of action in fast-killing bacteria through membrane permeation. However, several barriers to AMP development limit its clinical application. This application aims to overcome current AMP limitations to develop a safe and effective broad-spectrum antimicrobial against MDR Gram-negative bacterial infection. Our novel peptide therapeutics A4-AMP antibiotics (A4X) is a new generation of computationally engineered AMPs (eAMPs) derived from the antimicrobial motif, alpha-4, of a natural human host defense protein SPLUNC1 with negligible toxicity to mammalian cells. The extensive results from our studies demonstrate that our current lead candidate displays superior antibacterial activity to standard of care (SoC) antibiotics in over 500 clinical isolates of difficult-to-kill MDR Gram-negative pathogens obtained from hospitals and the CDC & FDA Antibiotic Resistance Isolate Bank. Our A4X lead also has a much lower tendency to develop resistance than SoC antibiotics. The A4X lead is safe and well tolerated when intravenously administered to mice and rats, with a four times higher maximum tolerated dosage than colistin, a last resort antibiotic, in mouse blood circulation. Moreover, we have demonstrated the efficacy of the A4X lead against Klebsiella pneumoniae and Acinetobacter baumannii in mouse models of bacteremia and respiratory infection. In this project, we will carry out preclinical and pre-IND non-clinical development activities and perform structure-activity relationship (SAR) based optimization of the current A4X lead to advance the preclinical development and to determine the clinical utility. We will extensively examine the safety, pharmacokinetic/pharmacodynamic, and efficacy of these novel antimicrobial agents in small and large animals of the most effective A4X. The targeting bacteria are the MDR strains of Gram-negative species on the CDC's urgent pathogen threats list and WHO's the most critical global priority 1 pathogens list (carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumonia, and Escherichia coli) and, including resistant strains to colistin. This proposal targets the urgent unmet global medical need for novel antibiotics and addresses the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria in a timely manner. Successful completion of these studies will have an enormous impact on developing a novel class of antibiotics capable of fighting MDR superbugs.


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 = $0 )
2026	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	11/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $840,040 )
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	001	3	9/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$840,040
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	9/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $840,040

Issue Date FY: 2024 ( Subtotal = $867,033 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	7/3/2024	NON-COMPETING CONTINUATION	$867,033
														Subtotal = $867,033

Issue Date FY: 2023 ( Subtotal = $880,743 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	7/31/2023	NEW	$880,743
														Subtotal = $880,743

Grand Total All Awards = $2,587,816

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Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms

Award Number: R01AI176537

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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