Date of Award

2026

Document Type

Thesis

Degree Name

MS in Pharmaceutical Science

Department

Pharmaceutical Sciences

First Advisor

Nitesh K Kunda

Second Advisor

Hyunah Cho

Third Advisor

Sabesan Yoganathan

Abstract

Tuberculosis (TB) is a deadly disease primarily targeting the lungs and has plagued the lives of millions of people around the world. TB remains a constant threat as the world’s leading cause of death from a single infectious agent after COVID-19. Available treatment regimens suffer from drug resistance and lengthy therapy, limiting patient compliance. TB’s resistance to most oral first-line drugs and their associated adverse effects requires an alternative therapeutic strategy. Herein, we explored novel drug combinations and employed inhaled delivery to limit resistance and minimize adverse effects. Further, we hope that this therapeutic strategy will specifically target latent TB infection, aiming to eliminate persistent bacteria residing in the lungs before reactivation. Linezolid (LZD), an antibiotic FDA-approved in 2000, is effective against multidrug resistant tuberculosis. Nisin (NP), an antimicrobial peptide, has shown potent antibacterial activity, presenting a promising approach towards treating tuberculosis. Through an optimized dry powder inhaler formulation, the combination of these drugs offers a new and improved way to deliver and treat TB. The resazurin-based microtiter assay was used to determine minimum inhibitory concentrations of both drugs, individually and in combination, against H37Ra. The REMA assay and the fractional inhibitory concentration index indicated that the drugs work synergistically at a ratio of LZD:NP-1.3:1, potentiating the therapeutic efficacy against TB. The drugs were combined with the excipients mannitol, L-Leucine, and trehalose (75:15:10) and spray-dried to obtain a dry powder for inhalation. Dry powder was evaluated by differential scanning calorimetry, powder x-ray diffraction, and thermogravimetric analysis. The formulation’s lung deposition profile was investigated using the Next Generation Impactor operated at 60 L/min. The spray-dried powder demonstrated transformation of crystalline materials into an amorphous form, with a residual moisture content of 1.8 %w/w. In vitro studies confirmed preserved antimicrobial efficacy post spray drying, showing efficient lung deposition with a mass median aerodynamic diameter of ~2 µm and fine particle fraction of ~80 %w/w. Together, these findings highlight the strong synergistic interaction between linezolid and nisin against Mycobacterium tuberculosis, representing a significant step forward in the pursuit of more effective, localized therapy for tuberculosis delivered directly to the site of infection.

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