# JHU- Optimal regimen development on a Ribosome inhibitor backbone.

> **NIH NIH U19** · GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT · 2020 · $505,143

## Abstract

PROJECT SUMMARY
Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes more deaths worldwide
than any single infectious agent. The rifamycin-based standard-of-care (SOC) regimen is efficacious but
requires 6 months of treatment, making it difficult to implement globally. Although high-dose rifamycin regimens
that may shorten treatment to 4 months are currently being trialed, neither these regimens nor the SOC will
benefit patients with rifamycin-resistant or multidrug-resistant (MDR-) TB, of which approximately 600,000 new
cases occurred in 2016. Current MDR-TB treatment regimens are toxic, require 9-24 months of administration
and cure only about 50% of patients. The availability of new regimens containing 3 or more novel drug classes
without pre-existing resistance could be transformational, especially if the treatment-shortening effects of
rifamycins could be replaced. The overall objectives of the consortium are (i) to discover and develop novel TB
drug candidates targeting various aspects of bacterial proteostasis (the capacity to coordinately synthesize and
degrade proteins), and (ii) to combine these candidates into novel 3- or 4-drug regimens capable of shortening
the treatment of drug-susceptible or RR-TB. Projects 1-3 will focus on the identification and advancement of
preclinical candidates, each targeting a component of the proteostasis machinery ([1] ClpC1, [2] ClpP1P2
protease, [3] RNA polymerase). Using a combination of an in vitro pharmacodynamics system (hollow fiber
model) and 3 complementary murine TB models (“standard” BALB/c mice, C3H3B/FeJ mice with more human-
like caseous [necrotic] lung lesions, immunocompromised nude mice), Project 4, which is described in this
application, will (1) characterize the exposure-response relationships that govern bactericidal activity,
resistance suppression and, in the case of TBI-223, toxicity of lead compounds emerging from Projects 1-3
plus TBI-223, the TB-focused oxazolidinone, which is already a pre-clinical candidate sponsored by TB
Alliance, (2) evaluate the impact of caseating lung lesions on these exposure-response relationships, and (3)
develop the most effective drug combinations containing the optimal doses of pre-clinical candidates emerging
from Projects 1-4 and evaluate their treatment-shortening potential relative to the SOC in predictive murine
models. The overarching goal is to develop one or more pharmacodynamically-optimized, universally active,
treatment-shortening regimens targeting Mtb proteostasis. Because this effort will occur in the context of a
robust, highly collaborative TB drug development program sponsored by TB Alliance pre-clinical candidates
emerging from Projects 1-4 may also be combined with other promising pre-clinical leads/candidates and
clinical candidates that target mechanisms other than proteostasis, thus amplifying the potential opportunities
for discovery of transformational regimens.

## Key facts

- **NIH application ID:** 9904485
- **Project number:** 5U19AI142735-02
- **Recipient organization:** GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
- **Principal Investigator:** ERIC L NUERMBERGER
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,143
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904485

## Citation

> US National Institutes of Health, RePORTER application 9904485, JHU- Optimal regimen development on a Ribosome inhibitor backbone. (5U19AI142735-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904485. Licensed CC0.

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