# RP2: Targeting genes and pathways for autophagy-dependent inhibition of bacterial infection

> **NIH NIH U19** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $1,720,690

## Abstract

PROJECT SUMMARY – RP2: Emerging drug-resistant pathogens have outpaced drug discovery, which poses
significant challenges for the development of safe and efficacious drugs. Our strategic approach addresses
challenges in drug discovery by integrating human genetics, functional genomics, novel animal models, and
innovative chemistry. Specifically, RP2 aims to develop host-directed therapeutics that harness innate
intracellular defense mechanisms through induction of autophagy for the treatment of bacterial pathogens
including S. Typhimurium, L. monocytogenes, S. aureus, multiple-drug-resistant strains thereof, and additional
priority pathogens with RP1, RP3, and RP4. During the previous CETR funding period we have (1) completed 3
small molecule screens to identify autophagy-dependent anti-infective molecules, (2) completed several
CRISPR screens to identify new targets controlling selective autophagy and lysosome homeostasis, and (3)
leveraged human genetics and functional genomics to identify novel targets for therapeutic induction of
antibacterial autophagy. Collectively, these studies advanced our objective of developing autophagy-directed
therapeutics by generating novel lead compounds from phenotypic screens and precision targets from functional
genomics. Moreover, our work has uncovered novel regulatory mechanisms governing autophagy and translated
these discoveries to identify new points of entry for autophagy therapeutics. Our collaboration with RP1, RP3
and RP4 led to the discovery of small molecules that augment innate intracellular defense against diverse
pathogenic microorganisms, including M. tuberculosis, S. flexneri, S. Typhimurium, arboviruses, norovirus, and
T. gondii. In addition, we have partnered with Novartis to advance lead compounds directed at novel targets and
to facilitate IND-enabling studies. In this CETR proposal, we will advance these autophagy-dependent anti-
infective molecules using innovative chemistry (RP5) and validate new therapeutic targets from functional
genomic and human genetic studies. We propose to leverage discoveries from the previous CETR Program to
advance: Aim 1: medicinal chemistry to progress primary screen hits from three independent autophagy screens
(LC3 puncta, NDP52-Salmonella co-localization and GPR65 agonist) to lead candidate autophagy-dependent
broad-spectrum anti-infectives for in vitro and in vivo efficacy studies; Aim 2: development of targeting strategies
to induce autophagy through TFEB, a master transcriptional regulator of autophagy and lysosome biogenesis
genes; Aim 3: validation of novel genes identified from functional genomic and human genetic studies as
therapeutic targets for antibacterial autophagy; and Aim 4: validation of novel anti-infective candidates generated
by RP1-RP5 as inducers of anti-bacterial autophagy using in vitro and in vivo models. Together, our CETR team
and industry partners are uniquely positioned to rapidly advance new treatments for emerging pathogens a...

## Key facts

- **NIH application ID:** 10144385
- **Project number:** 5U19AI142784-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ramnik J Xavier
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,720,690
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144385

## Citation

> US National Institutes of Health, RePORTER application 10144385, RP2: Targeting genes and pathways for autophagy-dependent inhibition of bacterial infection (5U19AI142784-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144385. Licensed CC0.

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