# High content, high throughput, diversity screen for novel anti-tubercular agents targeting intracellular bacteria

> **NIH NIH R21** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $295,350

## Abstract

Summary
Tuberculosis remains a major global health burden with 10 million new cases in 2019 and a latently-infected
population of billions. Deaths from tuberculosis now exceed those from HIV (1.2 million in 2019). Mycobacterium
tuberculosis, the causative agent, is a sophisticated pathogen which can persist for decades in the human host
and which requires lengthy treatment for cure with multiple antibiotics.
One of the features of M. tuberculosis is its ability to survive and replicate inside human cells, including
macrophages, one of the normal host defense mechanisms against infection. Intracellular bacteria are a specific
population which can be hard to kill, in part due to the requirement that molecules enter eukaryotic cells, and in
part due to the different physiological state in which the bacteria persist. Increasing evidence points to a higher
level of antibiotic tolerance in intracellular bacteria, as well as increased heterogeneity.
In order to find new agents, we developed a phenotypic screening method utilizing high content screening to
monitor bacterial and eukaryotic cell survival simultaneously. We ran a pilot screen to identify novel chemical
inhibitors of mycobacterial intracellular replication. We found several series of interest and selected three series
with attractive physicochemical properties. Based on our initial success we propose to expand our effort to run
a larger diverse screening set.
The overall aim of this proposal is to screen a diversity set of molecules against intracellular Mtb and to evaluate
and prioritize hits for future work. We will combine biological activity, profile, mode of action and physicochemical
properties to select series with the most promise. The major outcome of this exploratory proposal will be novel
chemical matter ready to enter the discovery pipeline.

## Key facts

- **NIH application ID:** 10526217
- **Project number:** 1R21AI166092-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Tanya Parish
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $295,350
- **Award type:** 1
- **Project period:** 2022-05-12 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526217

## Citation

> US National Institutes of Health, RePORTER application 10526217, High content, high throughput, diversity screen for novel anti-tubercular agents targeting intracellular bacteria (1R21AI166092-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10526217. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*