# Antimicrobial evaluation and development

> **NIH NIH P01** · NORTHEASTERN UNIVERSITY · 2020 · $664,543

## Abstract

Abstract 
Drug-resistant pathogens are causing a human health crisis. The overall goal of this Program is to resolve the 
bottleneck in the antimicrobial pipeline by developing an effective platform to discover novel compounds 
produced by an untapped source of chemical diversity, uncultured bacteria. The goal of this component project 
is to identify the mode of action of known antimicrobials with unknown target; and compounds produced by 
uncultured bacteria. Natural products have been all but abandoned by the Industry due to overmining of 
culturable bacteria and diminishing returns, but surprising discoveries keep coming from this group of 
compounds, both new and old. We discovered that acyldepsipeptide is capable of killing dormant persisters 
and sterilizes an incurable biofilm infection activating proteolysis. Novel species-selective compounds have 
been described – cyclomarin corrupts the essential ClpP1P2C1 protease of M. tuberculosis and lassomycin, 
which we recently isolated from an uncultured bacterium, inhibits this protease and simultaneously activates its 
ATPase, resulting in killing dormant cells. Aspergillomarasmine, a rediscovered old compound, inhibits metal 
β-lactamases which are insensitive to available therapies. Finally, we recently discovered teixobactin, a novel 
inhibitor of peptidoglycan synthesis from Elephtheria terrae, an uncultured β-proteobacterium. The compound 
binds to both lipid II and lipid III and is essentially free of resistance. We will undertake a large effort to identify 
the MOA of 500 known compounds with unknown targets. Their transcriptomes (Project II) will indicate 
specificity of action, and candidates will be evaluated in this project. Resistant mutants will be obtained, and 
sequencing of the target will provide independent confirmation. The MOA of a selected number of attractive 
candidates for development will be studied in more detail. This will considerably enrich our knowledge of what 
evolution determined to be a good target and facilitate the determination of MOA of new compounds produced 
by uncultured bacteria. Laborious chemical dereplication is a bottleneck that severely limits the rate of 
discovery of natural products. Rapid detection of the likely MOA of compounds present in extracts and 
fractions by transcriptome analysis (Project II) will resolve this bottleneck. Candidate leads from both old 
known compounds and the ones we discover from uncultured bacteria will be characterized in vitro and in vivo 
for potency, toxicity, and efficacy. For compounds with bactericidal activity, we will examine in detail activity 
against dormant persister cells and biofilms. Compounds that show good efficacy will become validated leads 
for advanced drug development. Unleashing the production potential of uncultured bacteria is likely to tip the 
balance in the standoff with pathogens in our favor. Determining the MOA of candidate compounds, together 
with their in vitro and in vivo propert...

## Key facts

- **NIH application ID:** 9933781
- **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:** $664,543
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933781

## Citation

> US National Institutes of Health, RePORTER application 9933781, Antimicrobial evaluation and development (5P01AI118687-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9933781. Licensed CC0.

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