Thursday, December 26, 2024
12/26/2024
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.
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