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Investigating beta-hairpin antimicrobial peptide membrane activity and toxicity.

Award Number: K22AI179937
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Investigating beta-hairpin antimicrobial peptide membrane activity and toxicity. - Project Summary My immediate career goals are 1) to obtain a tenure track position as a principal investigator and 2) to improve our understanding of the structure and function of β-hairpin antimicrobial peptides to help combat antibiotic resistant pathogens. My previous expertise, along with the career development laid out in this proposal, will allow me to complete the proposed research strategy and achieve these two immediate goals. New strategies and methods for antibiotic discovery are critically needed. Macrocyclic peptides are a promising class of antibiotic because they can target sites refractory to small molecule inhibition; however, their large size limits their ability to bypass membranes and access intracellular targets. Macrocyclic cationic antimicrobial peptides (CAMPs) are capable of penetrating bacterial membranes, but often have associated toxicity, making them more difficult to use clinically. A small class of CAMPs with cyclic β-hairpin structure (β- AMPs) access intracellular targets through bacterial membrane disruption and have a wide range of associated toxicity. Unfortunately, the rarity of this class prevents our understanding of how their amino acid sequence dictates their antibacterial potency and mammalian cell toxicity. I have helped developed a new synthetic macrocyclic peptide screening technique which has identified thousands of synthetic β-AMPs, expanding sequence information and allowing us to begin analyzing how their amino acid sequence impacts their antibacterial potency, cell membrane specificity, and ultimately their therapeutic potential. During Phase I of this proposal, I plan to biochemically analyze a newly acquired dataset of putative β- AMPs with diverse antibacterial potency and mammalian cell toxicity and use this data to train a machine learning algorithm to identify sequence features promoting antibacterial specificity. The in vivo activity of lead peptides will then be examined using the Galleria mellonella infection model. During Phase II, I will examine how β-AMPs interact with and permeate cell membranes composed of different lipids using strains with genetically modified lipopolysaccharide, in vitro liposome disruption assays, and ultraviolet photodissociation mass spectrometry. This will help us understand how β-AMPs overcome traditional methods of CAMP resistance and have an ability to selectively target bacterial cell membranes. Lastly, through modification of our screening technique, I have generated predictive data for how over 7,000 mutational variants of one promising natural β-AMP's amino acid sequence impacts its antimicrobial activity. I plan to evaluate the accuracy of these predictions through biochemical evaluation of 48 of the 7,000 variants. Differences in the toxicity and membrane specificity of this group will also be evaluated and compared to the native sequence to better understand how certain residues impact therapeutic potential.


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: 2025 ( Subtotal = $108,000 )
2025	2025	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	2	8/20/2025	NON-COMPETING CONTINUATION	$108,000
														Subtotal = $108,000

Issue Date FY: 2024 ( Subtotal = $158,800 )
2024	2024	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	1	8/30/2024	NEW	$158,800
														Subtotal = $158,800

Grand Total All Awards = $266,800

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Investigating beta-hairpin antimicrobial peptide membrane activity and toxicity.

Award Number: K22AI179937

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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