# Antibiotic dereplication by transcriptome analysis

> **NIH NIH P01** · NORTHEASTERN UNIVERSITY · 2020 · $605,144

## Abstract

Antibiotic resistant pathogens are rapidly spreading, creating a human health crisis. The significance of the 
problem is underscored by a recent President's Executive Order “Combating Antibiotic-Resistant Bacteria”, 
which calls for developing novel therapeutics. We currently lack an effective platform for antibiotic discovery, 
and the paucity of good starting compounds has been widely viewed as the main bottleneck for producing new 
therapeutics. Natural products have been the main source of novel compounds, but they were over mined half 
a century ago. Uncultured bacteria represent 99% of the total biodiversity. Methods to grow them have been 
developed by our collaborators on this Program, and several exciting compounds have been discovered 
(Projects I, III). What has been lacking however is an effective method to identify early on, the potential value 
of a compound in an extract of a producing isolate. We reason that the discovery bottleneck can be resolved 
by early biological dereplication, using transcriptome analysis of extracts to report on the mode of action (MOA) 
of a compound. This is immediately useful information, which automatically discards known and toxic 
compounds, and points to compounds hitting a new target, or acting in a new way against a known one. We 
validated this approach in a pilot study and will develop transcriptomics into a robust drug discovery 
dereplication method. We will build a database of transcription profiles produced by antibiotics with a known 
MOA and targets. This database will facilitate analysis of unknowns. In addition, we prioritized 500 
antimicrobials for transcription profiling based on in silico analysis of their suitability for drug development. 
Compounds will be added to a growing culture of an Escherichia coli and/or a Staphylococcus aureus strain, 
and transcriptome profiles of the antimicrobial challenged strains will be obtained. The large database resulting 
from this study will considerably enrich our knowledge of antibiotic targets and will identify candidate 
compounds for development. In parallel, we will obtain transcription profiles produced by fractionated and 
unfractionated extracts from uncultured bacteria (Project I). Extracts that produce transcriptomes clearly 
indicating the presence of a new compound hitting a known or new target will be given priority. We will 
evaluate and implement several computational tools to assign MOA. The result of this project will be a large 
and growing database of transcription profiles of antibiotics and antimicrobial compounds and efficient 
determination of which compounds produced in the antimicrobial screening pipeline of Project 1 are novel and 
are strong lead candidates. Coupling this Project to the rich source of novel compounds of Project 1 has 
potential for solving the two major impediments for new drug discovery and potential to thus bring on a new 
golden age of antimicrobial drug discovery.

## Key facts

- **NIH application ID:** 9933780
- **Project number:** 5P01AI118687-05
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Karen E. Nelson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,144
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933780

## Citation

> US National Institutes of Health, RePORTER application 9933780, Antibiotic dereplication by transcriptome analysis (5P01AI118687-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933780. Licensed CC0.

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