# Resolving the bottleneck in antibiotic discovery

> **NIH NIH P01** · NORTHEASTERN UNIVERSITY · 2020 · $1,807,186

## Abstract

Abstract
Most antibiotics resulted from the Waxman platform, screening of soil microorganisms, but this limited resource
was overmined by the late 60s. In the absence of a platform, compounds are introduced slower than
pathogens acquire resistance, and the result is a human health crisis. The recent President's executive order
“Combating Antibiotic-Resistant Bacteria” underscores the significance of this problem. In this Program, we will
develop an effective discovery program based on exploiting uncultured bacteria to resolve the bottleneck of
antimicrobial drug discovery.
 Uncultured bacteria are an untapped source of secondary metabolites, and we developed methods to
grow them and mine for antibiotic discovery. We discovered 25 new compounds from this source so far,
including lassomycin, a novel compound with specific activity against the ClpP1P2C1 protease of M.
tuberculosis; and teixobactin, a novel inhibitor of peptidoglycan synthesis which is essentially free of resistance
development. However, the real potential of uncultured bacteria remains unrealized - the background of
knowns and toxic compounds has been the main bottleneck even for this untapped source of chemical
diversity. We propose to solve this problem by introducing transcriptome analysis as a rapid tool to identify
promising compounds from uncultured bacteria. Compounds affecting the same target produce distinct
transcription profiles that cluster together. This approach allows us to classify compounds as known; novel
hitting a known target; novel hitting a new valuable target; hitting an undesirable target; or a nuisance
compound lacking specificity. In a pilot study, we determined that crude extracts from producing strains can be
used to generate transcriptome profiles in a test organism to identify targets, and deduce the presence of a
potentially valuable compound. In the proposed project, we will create a database of transcription profiles from
known antimicrobials, develop effective computational tools for transcriptome analysis, and will interrogate
transcriptomes from a large number of extracts and their fractions from uncultured bacteria. Lead molecules
will be validated in vitro and in an animal efficacy model. The end result of the project will be a novel discovery
platform, new targets, and lead compounds for drug development. The project is a collaboration between Kim
Lewis, PD/PI (NU), an expert in antimicrobial drug discovery and resistance; Karen Nelson, Co-Investigator
(JCVI), an expert in genomics, meta-omics approaches and computational biology; and Amy Spoering, Co-
Investigator (NovoBiotic), an expert in drug discovery from uncultured bacteria. These experts collaborated on
producing preliminary data for this Program.

## Key facts

- **NIH application ID:** 9933768
- **Project number:** 5P01AI118687-05
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Kim Lewis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,807,186
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933768

## Citation

> US National Institutes of Health, RePORTER application 9933768, Resolving the bottleneck in antibiotic discovery (5P01AI118687-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9933768. Licensed CC0.

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