# TB Alliance - Targeting Transcription Inhibition of RNAP

> **NIH NIH U19** · GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT · 2020 · $167,355

## Abstract

Project Summary
Bacterial RNA polymerase (RNAP) is an established target for broad-spectrum antibacterial therapy, including
in Mycobacterium tuberculosis (Mtb). Rifampicin (RIF) is a natural product inhibitor of RNAP and a cornerstone
component of the WHO-recommended, first-line, short-course, 6-month, standard-of-care (SoC) TB regimen of
RIF, isoniazid, pyrazinamide, and ethambutol (RHZE). RIF is facing growing drug resistance development in
the clinic, including multiple-drug resistance (MDR-TB), defined as tuberculosis caused by an organism that is
resistant to both RIF and isoniazid. RNAP is essential for bacterial growth, making its inhibition a lethal event,
including under non-replicating conditions, which is also the most likely reason that RIF is the most sterilizing
agent in the SoC regimen that is credited for reducing the duration of therapy from 18-24 down to 9-12 months.
This is also the reason that therapy for MDR-TB, where RIF is obsolete, requires treatment durations of 18-24
months, with less efficacious, and poorly tolerated drugs and often with inferior cure rates. Since RIF is key in
the short-course, 6-month duration of the modern first-line regimen for drug-susceptible TB, loss of RIF
susceptibility, as in MDR-TB, mandates the extended therapy of 18 or more months with second-line drugs and
that is associated with poorer outcomes. Restoring even a portion of the treatment-shortening capacity of RIF
could dramatically shorten the duration of MDR/XDR-TB treatment, reduce the selection of additional second-
line resistance and greatly improve outcomes. There is therefore an urgent need for novel anti-TB agents that
inhibit Mtb RNAP and produce the same therapeutic efficacy as RIF, but with novel binding sites on Mtb RNAP
that are distinct from the RIF binding site to avoid cross-resistance to allow efficacy against MDR/XDR-TB. We
have identified a series of small molecules that are non-rifamycin, non-RIF cross-resistant, RNAP inhibitors
that bind at a non-overlapping site with RIF on Mtb RNAP. The proposed project in collaboration with Cores A,
B, and C will deliver a safe drug development candidate with potent activity against both replicating and non-
replicating Mtb. The resulting candidate will have demonstrated sterilizing efficacy within novel 3- and 4-drug,
proteostasis-disrupting combinations that produce relapse-free cure in mouse Mtb infection models with
durations shorter than the SoC regimen, including against MDR/XDR-TB, with the propensity to suppress
resistance development. The other drug candidates in the combination will emerge from accompanying
Projects 1 and 2 (modulators of ClpC1 and Clp P1/P2), and a safer oxazolidinone currently undergoing IND-
enabling toxicity studies (Ribosome inhibitor) as described in Project 4.

## Key facts

- **NIH application ID:** 9904484
- **Project number:** 5U19AI142735-02
- **Recipient organization:** GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
- **Principal Investigator:** KHISIMUZI E. MDLULI
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,355
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904484

## Citation

> US National Institutes of Health, RePORTER application 9904484, TB Alliance - Targeting Transcription Inhibition of RNAP (5U19AI142735-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904484. Licensed CC0.

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