# Antibiotic discovery from a new genus of uncultured bacteria.

> **NIH NIH R43** · NOVOBIOTIC PHARMACEUTICALS, LLC · 2021 · $296,521

## Abstract

Abstract: The current antimicrobial resistance crisis is caused by the rise and spread of drug resistant
pathogens. According to the WHO, drug-resistant E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, S. aureus
and M. tuberculosis are of especial concern. We are now facing pathogens that are resistant to most, or all,
currently available antibiotics. Slowing down of discovery and a very modest pipeline of novel compounds are
responsible for the crisis. The last novel compound active against Gram-positive pathogens introduced to the
clinic, daptomycin, was discovered over 30 years ago; the last class of compounds acting against Gram negative
bacteria, the fluoroquinolones, was developed in the 60s. We have used a number of approaches to exploit an
untapped source of antimicrobials – uncultured bacteria that make up the majority of species of microorganisms.
Cultivation in situ led to the discovery of >30 new compounds. One of these, teixobactin, represents a novel
class of cell wall acting antibiotics and is in IND-enabling studies against MRSA Staphylococcus aureus.
Teixobactin has a unique property, there is no detectable resistance to this compound. Teixobactin binds two
immutable targets, lipid II, precursors of peptidoglycan, and lipid III, precursor of wall teichoic acid, accounting
for lack of resistance (Ling et al., 2015). Novo29 is another novel compound that binds the same targets.
Interestingly, both antibiotics are produced by members of a new genus, Eleftheria, a Gram-negative -
proteobacteria. Given their ability to produce unusual compounds, we assembled an additional set of Eleftheria
isolates from our collection and screened them for antimicrobials, but did not initially observe activity. Whole
genome sequencing shows that Eleftheria contain PKS and NRPS operons for the production of secondary
metabolites that appear to be silent. We then used media spiked with different amino acids to induce expression,
and this led to the production of several antimicrobials that we are currently characterizing. Our preliminary
findings suggest that Eleftheria is an attractive genus of bacteria to search for novel antibiotics. The goal of this
Phase I project is to examine the potential of this genus to produce antibiotics and identify a novel lead compound
for further development. We identified the antibiotic resistance profile of Eleftheria, and will use this to selectively
isolate additional members of this group. Spiking of amino acids, as well as mutagenesis will be used to turn on
silent operons. The search will be guided by whole genome analysis of isolates, which will indicate the presence
of biosynthetic gene clusters. We will focus on isolates with BGCs that lack close homologs. Bioassay-guided
fractionation will lead to purification of compounds. Spectrum of activity will be determined, and we will give
preference to compounds acting against Gram negative bacteria. Compounds with minimal cytotoxicity will be
advanced to mode of...

## Key facts

- **NIH application ID:** 10148638
- **Project number:** 5R43AI152675-02
- **Recipient organization:** NOVOBIOTIC PHARMACEUTICALS, LLC
- **Principal Investigator:** Amy Lynn Spoering
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $296,521
- **Award type:** 5
- **Project period:** 2020-04-22 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148638

## Citation

> US National Institutes of Health, RePORTER application 10148638, Antibiotic discovery from a new genus of uncultured bacteria. (5R43AI152675-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10148638. Licensed CC0.

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