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Biomimetic Peptide Aerosols for Rapid Clearance of Pulmonary MDR Tuberculosis

Award Number: R01AI165996
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: 11/19/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Biomimetic Peptide Aerosols for Rapid Clearance of Pulmonary MDR Tuberculosis - PROJECT SUMMARY Multidrug-resistant Tuberculosis (MDR-TB), which accounts for ~20% of recurrent TB cases and is diagnosed in 400,000 patients each year, represents an urgent global health priority that threatens to undermine US TB elimination strategies. Key to MDR-TB transmission is disruption and non-compliance with standard therapeutic regimens, which are lengthy (up to 24 months) and require high daily doses of antibiotics. The goal of this project is to develop an aerosolizable, narrow-spectrum antimicrobial biomaterial that can be paired with approved TB antibiotics to rapidly clear pulmonary MDR-TB and dramatically shorten the course of treatment. Fundamental to this strategy is a new class of protein-mimetic host defense peptides we have engineered de novo to undergo instructed self-assembly within the mycolic-acid rich outer membrane of Mycobacterium tuberculosis (Mtb). We have shown that our lead candidate, MAD1, elicits TB-specific bacteriolysis within minutes of exposure, without collateral toxicity towards protective respiratory commensals and host lung tissue. Further, these novel peptides synergistically enhance the activity of clinical antibiotics to achieve nanomolar anti-TB efficacy. However, these synthetic peptides have pharmacokinetic liabilities that include rapid clearance and limited pulmonary bioavailability, and there remain gaps in our knowledge regarding their mechanism of action when combined with other drugs. The objectives of this application are to: (i) more deeply investigate the mode of action (MoA) and drug interactions (e.g. synergy) of our lead compound MAD1 in Mtb, (ii) improve its ADME (absorption, distribution, metabolism and elimination) properties and pharmacokinetic parameters through sequence optimization and formulation into novel biomaterial aerosols, and (iii) determine the safety profile and efficacy of lead formulations in disease-relevant preclinical models. We will accomplish these objectives over three aims. In aim 1, artificial intelligence-guided structure-based sequence screening and recombineering assays will optimize MAD1’s potency against Mtb and drug-resistant strains, as well as inform on MoA. Whole-genome sequencing of resistant strains generated during these studies will characterize possible resistance mechanisms and determine the resistance frequency. Aim 2 will develop inhalable formulations of MAD1 and antibiotics utilizing our proprietary aerogel delivery system designed to exploit a key metabolic vulnerability of Mtb for rapid and pathogen-specific pulmonary therapy. Combination bacteriologic studies will assess potential for synergy towards MDR-TB and persister cells in macrophages. In aim 3, we assess the pulmonary pharmacokinetic parameters of prioritized aerogel formulations with the goal of optimizing the lung bioavailability and residence/clearance kinetics of the therapeutic carrier. We will evaluate the safety of therapeutic formulations via a series of assays (histology, pulmonary function, immunogenicity) and assess in vivo efficacy in several murine models of acute and chronic TB infection.


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 = $448,864 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	4	1/9/2025	NON-COMPETING CONTINUATION	$448,864
														Subtotal = $448,864

Issue Date FY: 2024 ( Subtotal = $478,139 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	001	3	5/13/2024	NON-COMPETING CONTINUATION	$47,814
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	3	10/24/2023	NON-COMPETING CONTINUATION	$430,325
														Subtotal = $478,139

Issue Date FY: 2023 ( Subtotal = $394,630 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	2	10/31/2022	NON-COMPETING CONTINUATION	$394,630
														Subtotal = $394,630

Issue Date FY: 2022 ( Subtotal = $396,522 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	1	11/19/2021	NEW	$396,522
														Subtotal = $396,522

Grand Total All Awards = $1,718,155

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Biomimetic Peptide Aerosols for Rapid Clearance of Pulmonary MDR Tuberculosis

Award Number: R01AI165996

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: 11/19/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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