# Target-based chemotherapeutics development against Mycobacterium tuberculosis

> **NIH NIH R21** · UNIVERSITY OF MISSISSIPPI · 2020 · $218,138

## Abstract

Target-based chemotherapeutics development against Mycobacterium tuberculosis
ABSTRACT
Tuberculosis (TB) has been a global burden for thousands of years that is currently costing 1.6 million lives every
year. The current therapies for TB are inadequate to control this epidemic and there is an urgent demand for the
development of new effective anti-TB drugs, now more than ever, to overcome the problems of antimicrobial
resistance. We have identified MraY as an attractive drug target, but one that is rather unexploited. MraY is
essential for the biosynthesis of the peptidoglycan of bacterial cell walls. The limitations of current nucleoside
MraY inhibitors are several: (i) poor in vivo efficacy; (ii) promiscuity (off-target activities); and (iii) accessibility
only by semi-synthesis or total synthesis (>20 steps). We hypothesize that using structural insights on
mechanism of MraY catalysis and inhibition, we could address those limitations and more importantly convert
the existing broad-spectrum and promiscuous antibacterials to design new MraY inhibitors with narrow-spectrum
activity against Mycobacterium tuberculosis (Mtb). The following aims will aid our discovery of new generations
of anti-TB drugs that act through inhibition of MraY enzyme. Aim1. Develop MraY inhibitors as narrow-spectrum
antibiotics against Mtb using structure-based design. We will utilize molecular modeling and docking studies on
the recently published X-ray crystal structures of MraY from Aquifex aeolicus and Clostridium bolteae and design
structurally simple analogues using a pharmacophore hybridization approach that will retain the key elements
required for binding to the active site of MraY protein and critical for Mtb inhibitory activity. We will perform
systematic structure-activity relationship studies to improve the inhibitory activity of the analogues against MraY
and against replicating and multi-drug resistant Mtb strains. Aim 2. Identify new inhibitors of MraYMtb using
protein-target-based virtual screening protocols. We will construct and validate homology models of MraYMtb
using molecular dynamics simulations, which will be used to screen small molecule databases to identify and
develop novel hits as MraY inhibitors. The outcome of these aims will establish a new strategy for TB therapy,
where antibiotic resistance is impeding our ability to effectively control this epidemic. Notably, MraY is a validated
target that is conserved in all bacteria and is not present in humans. Through this work, we will gain insight into
how structure-based rational drug design strategies can be used effectively to convert broad-spectrum
antibacterials to species-specific narrow-spectrum drug candidates and will provide a new therapeutic avenue
for treatment of drug-sensitive and drug-resistant TB cases. This proposal will provide a critical step in treating
other pathogenic and notoriously drug-resistant bacteria including methicillin-resistant Staphylococcus aureus,
Vancomycon-r...

## Key facts

- **NIH application ID:** 9955206
- **Project number:** 5R21AI142210-02
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI
- **Principal Investigator:** Sudeshna Roy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $218,138
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955206

## Citation

> US National Institutes of Health, RePORTER application 9955206, Target-based chemotherapeutics development against Mycobacterium tuberculosis (5R21AI142210-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9955206. Licensed CC0.

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