Date of Award
1-1-2023
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Sudeshna Roy
Second Advisor
John Rimoldi
Third Advisor
Davita Watkins
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Tuberculosis (TB) is a major global health burden. This airborne infectious disease is caused by Mycobacterium tuberculosis (Mtb) and resulted in 1.6 million deaths globally in 2021. The emergence and spread of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) underscores the urgent need to discover and develop new agents, particularly those with narrow spectrum activity and those acting by novel mechanisms. Although broad-spectrum antibacterials have been successful in treating drug-resistant bacterial infections, including TB, there is a push toward the discovery and development of anti-TB agents with narrow-spectrum activity. This approach aims to limit the spread of resistance across multiple bacterial species and mitigate the detrimental effect of broad-spectrum agents on the host microbiome. Moreover, these selective agents have a lower tendency to develop bacterial resistance, and the selectivity is even more pertinent in the long duration of treatment for TB.
Herein, the discovery and synthesis of a new series of 3-thio-1,2,4-triazoles that show narrow-spectrum inhibition of Mtb growth and survival is reported. Structure-activity relationship studies led to the identification of potent analogs displaying nanomolar inhibitor activity, specifically against Mtb. In another part of this work, isosteric replacement of the 3-thio-1,2,4-triazole core of the above series with cysteine led to a new class of compounds with micromolar activity against Mtb (IC50 3–90 μM). Furthermore, the discovery of narrow-spectrum inhibitors of MraY (phospho-MurNAc-pentapeptide translocase) was undertaken. This integral membrane protein is critical for the synthesis of the Mtb cell wall peptidoglycan and is a promising target against Mtb. Progress in the development of natural product nucleoside inhibitors of MraY and their analogs has been met with the challenges of structural complexity and poor in vivo efficacy. Using a structure-based drug design strategy, new non-nucleoside MraY inhibitors have been identified. This includes a new series of 1,2,4-triazole-based non-nucleoside MraY inhibitors, several of which demonstrated an IC50 < 200 μM against MraY and are potent against Mtb.
In conclusion, this work describes the discovery of new antitubercular agents with narrow-spectrum activity, new chemical scaffolds, or agents that inhibit MraY, which have the potential to become candidates for replenishing the depleting antitubercular armamentarium upon further optimization.
Recommended Citation
Berida, Tomayo Ireti, "Development of Narrow-Spectrum Agents and MRay Inhibitors Targeting Multidrug-Resistant Mycobacterium Tuberculosis" (2023). Electronic Theses and Dissertations. 2482.
https://egrove.olemiss.edu/etd/2482