# Macrocyclic proteasome inhibitors for treatment of tuberculosis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $254,250

## Abstract

Project Summary/Abstract
Existing medicines for tuberculosis are losing ground to drug resistance. There is intense need
to develop new regimens that include drugs active against Mycobacterium tuberculosis (Mtb)
cells in the slowly- or non-replicating states (for simplicity, “NR” states) associated with
phenotypic tolerance to most TB drugs. Our long-term goal is to develop anti-Mtb drugs that kill
NR Mtb populations to complement drugs that kill replicating Mtb populations. Mtb relies on
specific enzymatic pathways to survive the host stresses that make it NR. Among these is the
prokaryotic ubiquitin-like protein (Pup)-proteasome system discovered over several years
beginning in 2003. Although the Mtb proteasome is dispensable under standard growth
conditions, it has been validated as a drug target both genetically and pharmacologically: the
knock-out strain dies in the chronic phase of disease in mice, and we introduced several
classes of Mtb proteasome inhibitors that kill NO-stressed or starved Mtb in vitro. These
included the first inhibitors selective (>1000-fold) for the proteasome of a pathogen and not its
host, and the first agents to kill bacteria by inhibiting protein breakdown rather than protein
synthesis. Heretofore there have been only five broad classes of antibiotic targets: inhibition of
synthesis of nucleic acids, proteins, cell walls and folate, and disruption of membranes. Our
work has validated a fifth class: inhibition of a protein degradation pathway, and led to the
discovery by others of pathogen-selective proteasome inhibitors that kill the protozoal agents
of malaria, Chagas disease and Leishmaniasis. In this application, we will advance our newly
discovered novel class of peptidomimetics. We demonstrate that these inhibitors are highly
potent and species selective Mtb proteasome inhibitors. We propose to conduct lead
optimization to achieve oral bioavailability with safety for future in vivo efficacy studies in
mouse model of Mtb infection.

## Key facts

- **NIH application ID:** 10124264
- **Project number:** 5R21AI144552-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gang Lin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2020-03-09 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124264

## Citation

> US National Institutes of Health, RePORTER application 10124264, Macrocyclic proteasome inhibitors for treatment of tuberculosis (5R21AI144552-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10124264. Licensed CC0.

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