Date of Award
5-1-2026
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Sudeshna Roy
Second Advisor
Robert Doerksen
Third Advisor
John Rimoldi
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global public health concern and one of the leading causes of death from a single infectious agent worldwide. According to the World Health Organization (WHO) Global Tuberculosis Report, in 2024 approximately 10.8 million people developed TB and an estimated 1.25 million deaths were reported globally. The growing emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, combined with lengthy treatment regimens, drug toxicity, and poor patient compliance, has further complicated treatment and threatens global control efforts. These challenges highlight the urgent need for the development of new antitubercular agents with improved efficacy, shorter treatment durations, and novel mechanisms of action. This dissertation focuses on the design, synthesis, and biological evaluation of novel small-molecule growth inhibitors targeting multidrug-resistant Mtb, with the goal of identifying potent lead compounds with improved drug-like properties and therapeutic potential.
Herein, the discovery of cysteine-based amino acid mimetics as a novel class of small-molecule growth inhibitors is described. Guided by rational design and structure–activity relationship (SAR) studies, a series of analogs was synthesized and evaluated for inhibitory activity. Systematic structural modifications across key regions revealed important molecular features governing potency and selectivity, leading to several compounds exhibiting low micromolar to sub-micromolar activity with minimal cytotoxicity in mammalian cells. These findings provided valuable insight into structural requirements necessary for enhanced antimycobacterial activity and improved drug-like characteristics.
Building upon these findings, saturated nitrogen-containing scaffolds were further explored to improve potency, physicochemical properties, and pharmacokinetic profiles. A diverse library of analogs incorporating saturated nitrogen-containing cores was designed, synthesized, and evaluated through in vitro biological screening. Key substituents influencing antimycobacterial activity, as well as functional groups known to improve aqueous solubility and metabolic stability, were identified, resulting in compounds with improved potency in the microplate alamar blue assay (MABA). Selected lead compounds are undergoing further evaluation for absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, including in-house aqueous solubility and metabolic stability studies to assess drug-like characteristics and preclinical potential.
Collectively, the studies presented herein establish two novel small-molecule scaffolds with potent antimycobacterial activity and favorable preliminary pharmacological properties. These findings contribute to the growing pipeline of antitubercular agents and provide promising lead candidates for further optimization and development to address multidrug-resistant infections and improve global treatment outcomes.
Recommended Citation
Manning, Destinee Latrell, "Development of Small-Molecule Growth Inhibitors Targeting Multidrug-Resistant Mycobacterium Tuberculosis" (2026). Electronic Theses and Dissertations. 8846.
https://egrove.olemiss.edu/etd/8846