# Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

> **NIH NIH U19** · GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT · 2020 · $5,528,394

## Abstract

The main objective of the CETR is to modulate protein production and degradation as an integrated approach
to rapid sterilization of drug sensitive (DS) and drug resistant tuberculosis (DR-TB) with the ultimate goal of
delivering 2 investigational new drug (IND) applications and a regimen that will be effective against both DS
and DR-TB and could result in relapse-free cures of TB-infected mice in 2 months or less, while also
suppressing resistance development. Historically, TB treatment regimen development has been largely
empiric. Our current treatment arises from serial clinical trials performed over the course of decades. Recently,
we have accelerated this empiric process using a mouse model which, thus far, has excellent predictive power.
However, any rationale for these regimens is ex post facto - we really do not understand why certain
combinations are better than others. Here we will endeavor to devise a better regimen from first principles. We
know that inhibition of RNA polymerase (RNAP) is clinically proven to shorten therapy dramatically and that
rifampin synergizes with a variety of drugs. Using genetic studies, we have found that protein degradation is a
particularly vulnerable process as even modest inhibition of Clp protease activity results in cell death. We
reason that multiple insults in the “proteostasis” pathway that leads from transcription through translation and
protein turnover will likely result in more potent TB treatment regimens. Indeed, our preliminary in vivo data
suggest this is true. This multidisciplinary CETR consortium will bring together key expertise on three major
drug targets that constitute the complex and coordinated network of processes that maintain proteostasis in
TB. Through this highly interconnected set of projects and cores we will be able to: Identify modulators of the
Clp protease complex by discovering an orally active modulator of ClpC1, and a small molecule ClpP1P2
protease inhibitor (Project 1 and Project 2 and Cores A, B and C). Using structure guided drug discovery
approaches and the latest formulation technologies these modulators will be optimized and advanced to
preclinical candidate selection. We expect at least one preclinical candidate to emerge from these various
approaches. Identify novel RNAP inhibitors that bind and inhibit the enzyme at a non-overlapping site than
rifamycins that will therefore be effective against both drug-sensitive and DR-TB (Project 3 and Cores A, B,
and C). Use of structural information and computational chemistry will guide our effort to preclinical candidate
selection. Using an in vitro hollow fiber system and mouse Mtb-infection models, we will characterize the
PK/PD relationships that govern the anti-TB activity and suppression of drug-resistant mutants for each drug
candidate (ClpC1 modulators [Project 1], ClpP1P2 modulators [Project 2], RNAP inhibitors [Project 3] and a
safer oxazolidinone already identified and currently in IND enabling studies, [Proj...

## Key facts

- **NIH application ID:** 9904472
- **Project number:** 5U19AI142735-02
- **Recipient organization:** GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
- **Principal Investigator:** Nader Fotouhi
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $5,528,394
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904472

## Citation

> US National Institutes of Health, RePORTER application 9904472, Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb. (5U19AI142735-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904472. Licensed CC0.

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