De Novo Design and Delivery of Biomimetic Therapies for Pulmonary Tuberculosis
Open Access
- Author:
- Simonson, Andrew
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 15, 2020
- Committee Members:
- Scott H Medina, Dissertation Advisor/Co-Advisor
Scott H Medina, Committee Chair/Co-Chair
Daniel J Hayes, Committee Member
Pak Kin Wong, Committee Member
Ken Keiler, Outside Member
Jian Yang, Committee Member
Daniel J Hayes, Program Head/Chair - Keywords:
- Antimicrobial
Peptide
Tuberculosis
Biomaterials
Drug Delivery
Inhalable - Abstract:
- Tuberculosis, caused by Mycobacterium tuberculosis, is the leading cause of death globally by a single infectious agent, taking its toll disproportionately on low- and middle-income regions with poor medical infrastructure. This endless pandemic requires novel therapeutic approaches to address the pathophysiological challenges the bacteria presents. Beyond the growing issue of antimicrobial resistance worldwide, M. tuberculosis has a uniquely impenetrable envelope, can reside within the host individual’s immune cells to avoid detection, and can dormantly persist in a metabolically altered non-replicative state. Together, these unique characteristics require long, toxic regimens of antibiotic chemotherapy. Poor patient compliance, among other factors, is driving the emergence of multi-drug resistant tuberculosis. Thus, new treatment strategies are needed to regain control of the global tuberculosis burden. This work leveraged unique approaches in microbiology, peptide chemistry and material science to develop an inhalable delivery vehicle exhibiting potent and specific anti-tuberculous bioactivity through mechanisms unique from conventional anti-infectives. This ‘Trojan Horse’ style biomaterial selectively targeted infected tissues before directly exposing the invading pathogens to a novel antimicrobial peptide designed to physically disrupt the distinct mycomembrane layer. Importantly, this method afforded simple co-delivery of traditional antibiotics encapsulated within the micro-scale particle, potentially negating and circumventing antimicrobial resistance. Herein, I introduce the pathophysiology and current treatment modalities of pulmonary tuberculosis, as well as biotherapeutics gaining attention and the use of biomaterial scaffolds for antimicrobial applications. This will provide context for design requirements and potential stages in which to disrupt the infection cycle. Secondly, I detail the rational design of a biomimetic peptide, called MAD1, and subsequent elucidation of its antimycobacterial activity. This work provides evidence of peptide drug design through sequence and structural homology with species-specific proteins. Next, I cover the design and synthesis of the biomaterial platform, which will in turn serve as the basis of the tuberculosis-targeted formulation. Finally, I report the integration of the particle design with MAD1 and adaptation for combinatorial tuberculosis treatment. This work in its entirety represents a versatile platform with great potential to address significant hurdles in tuberculosis therapy and our struggle against drug resistance.