# Engineering probiotics for tuberculosis therapy

> **NIH NIH R21** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2022 · $289,699

## Abstract

PROJECT SUMMARY
The engineering of living cells and microbes is driving a new era of medicine. This transformative approach
allows for the genetic programming of living cells to intelligently sense and respond healthy and diseased envi-
ronments in the body. Bacteria have specifically generated significant recent interest due to their genetic tracta-
bility and ability to infiltrate disease sites. A multitude of studies have shown bacterial delivery of therapeutic
payloads selectively into tumor cores, demonstrating specificity and efficacy that is otherwise unattainable with
molecular-based therapeutics. Given this paradigm in cancer therapy, bacteria present a unique opportunity to
be engineered as intelligent delivery vehicles to inaccessible disease sites.
 We recently discovered that probiotic E. coli Nissle 1917 (EcN) selectively home to granulomas, pathological
regions developed at infection sites including tuberculosis. Tuberculosis kills 1.5 million people each year but
conventional antibiotics are limited by toxicity, long treatment courses, and drug resistance. Importantly, while
difficult for conventional therapeutics to reach, granulomas possess unique necrotic and hypoxic microenviron-
ment similar to tumors that supports selective bacterial colonization.
 The objective of this proposal is to engineer EcN to home to granulomas and locally produce therapeutics to
eliminate pathogenic Mycobacterium tuberculosis. We will use synthetic biology approaches to genetically engi-
neer EcN as an intelligent drug delivery vehicle. We will utilize hypoxia-sensing growth circuits that further restrict
probiotic growth the hypoxic, necrotic granuloma environment. Using a novel in vitro 3D coculture assay, we will
screen a library of antimicrobial proteins to identify the most potent antimycobacterial therapeutic candidates.
We will test the therapeutic efficacy of engineered E. coli using mycobacterium granuloma mouse models. This
fundamentally new approach to granulomatous disease will open up opportunities to utilize engineered bacteria
as therapeutic agent for granulomatous infections.

## Key facts

- **NIH application ID:** 10511520
- **Project number:** 1R21AI171819-01
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Tal Danino
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $289,699
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511520

## Citation

> US National Institutes of Health, RePORTER application 10511520, Engineering probiotics for tuberculosis therapy (1R21AI171819-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10511520. Licensed CC0.

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