# Siderophore-dependent inhibitors of Mycobacterium tuberculosis

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $198,000

## Abstract

Project Summary - Siderophore-dependent inhibitors of Mycobacterium tuberculosis
Mycobacterium tuberculosis (Mtb) is the leading cause of human deaths from an infectious
disease. The astronomical costs of treating tuberculosis patients infected with drug-resistant
Mtb42and the very long treatment times pose a huge financial burden on health care systems in
particular in developing countries. Even more challenging is the increasing number of infections
with extensively or totally drug-resistant Mtb that have become untreatable. Thus, the
development of new TB drugs, preferably against new drug targets, is urgent. Iron is acquired
by Mtb by secreting siderophores, small molecules with high affinity for iron called mycobactins
and carboxymycobactins and subsequent uptake of iron-loaded siderophores. We discovered
that genetic inactivation of the siderophore secretion system in Mtb leads to intracellular
accumulation of siderophores and self-poisoning of Mtb reducing its virulence in mice by more
than 10,000-fold. Based on this observation we have developed an innovative, whole-cell
screening assay to identify compounds which inhibit Mtb in a siderophore-dependent manner.
Screening of 300,000 compounds and subsequent structure-activity relationship (SAR) studies
yielded four lead compounds with exciting properties (novel mechanism of action, nanomolar
activities against Mtb, low toxicity and strong synergy with some TB drugs. These preliminary
results validated siderophore secretion as a novel and druggable target of Mtb. The aims of this
proposal are to examine the activity of siderophore-dependent inhibitors in a mouse model of
tuberculosis, to determine their activity against drug-resistant Mtb and to identify their molecular
targets.

## Key facts

- **NIH application ID:** 10199992
- **Project number:** 5R21AI153981-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** MICHAEL NIEDERWEIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $198,000
- **Award type:** 5
- **Project period:** 2020-06-22 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199992

## Citation

> US National Institutes of Health, RePORTER application 10199992, Siderophore-dependent inhibitors of Mycobacterium tuberculosis (5R21AI153981-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10199992. Licensed CC0.

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