# Siderophore Inhibitors for Tuberculosis that Block Mycobactin Biosynthesis

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $745,441

## Abstract

SUMMARY
Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-third of
humanity and is now the leading cause of infectious disease mortality by a single pathogen. Mtb requires iron
for survival and obtains this essential micronutrient in vivo through the synthesis, secretion, and re-uptake of
siderophores or small-molecule iron chelators known as the mycobactins. In preliminary studies using a
genetic approach, we have shown mycobactin biosynthesis is essential for Mtb infection in mice. We have
synthesized a selective nanomolar inhibitor of mycobactin biosynthesis termed Sal-AMS that targets the
enzyme MbtA, responsible for the first and committed biosynthetic step of the mycobactins. The objectives of
this application are: 1) to dramatically improve upon the in vivo efficacy of our lead compound Sal-AMS
through the optimization of its pharmacokinetic parameters and potency, 2) to more deeply illuminate the
mechanism of action and resistance in Mtb, 3) to determine the safety profile and potential drug-drug
interactions, and 4) to identify interactive effects with other TB drugs (i.e. synergy). We will accomplish the
overall objectives of this application by pursuing three specific aims. In aim 1, we will carry out an iterative
structure-based medicinal chemistry program to concurrently optimize pharmacokinetic (PK) parameters and
whole-cell activity using a combination of approaches including fluorination, structural simplification of the
nucleoside, and introduction of conformation constraints into the inhibitor. In aim 2, we will perform biochemical
and cellular studies to evaluate enzyme inhibition, target engagement, cellular accumulation, and whole-cell
activity against Mtb as well as drug-resistant strains. Generation of resistant strains followed by whole-genome
sequencing will be used to characterize potential resistance mechanisms and determine the resistance
frequency. Finally, combination studies with various first and second-line TB drugs will be undertaken to
assess potential for synergy. In aim 3, the siderophore inhibitors will be assessed in vivo to determine their
complete pharmacokinetic parameters with a goal to improve on the volume of distribution (Vd), intrinsic
clearance (CL), and bioavailability (F). We will conduct chronic toxicity studies and evaluate compounds
against a panel of assays (hERG, CYP inhibition, kinase panel) to ensure safety and selectivity. In vivo
efficacy studies will be done using a murine model of TB infection.

## Key facts

- **NIH application ID:** 10368998
- **Project number:** 5R01AI136445-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Courtney C Aldrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $745,441
- **Award type:** 5
- **Project period:** 2018-04-25 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368998

## Citation

> US National Institutes of Health, RePORTER application 10368998, Siderophore Inhibitors for Tuberculosis that Block Mycobactin Biosynthesis (5R01AI136445-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10368998. Licensed CC0.

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