# Development of Selective Ribosomal P-site Inhibitors

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

Project Summary
The long-term objective of this project is to develop a new class of broad spectrum antibiotics, focused on
Gram-negative bacteria and tuberculosis. In addition, the proposed project will teach how to optimize inhibitors
of the prokaryotic ribosome by defining critical interactions only possible in bacteria. Inspired by a natural
product, this class targets an unexploited binding site of the bacterial ribosome. With increasing reports of
resistance to frontline antibacterial therapies, there is a critical need for new agents, yet very little can be found
in the development pipeline. As a result, any new therapeutic that targets Gram-negative bacteria and/or
tuberculosis will address an unmet medical need.
A viable approach to discover new therapeutic leads is re-evaluation of existing, but under-scrutinized classes
of natural products. Through this approach a natural product scaffold was identified as a lead for a program
directed toward antibiotics for tuberculosis. Initial evaluation of activity against other bacteria indicated that the
antibacterial spectrum was limited to Mycobacterium spp. However, based on the chemical structure and
related compounds, we expected to be able to generate analogs with more broad spectrum activity.
In collaboration with Tom Steitz's lab at Yale, the structure of the initial scaffold and two analogues bound to
the ribosome were recently solved. The structural studies revealed that the natural product lead and analogues
bind to a highly conserved region of the peptidyl transferase center (PTC) in a manner that appears to convey
prokaryotic selectivity and which has not been exploited in current therapeutics. Targeting this highly
conserved region is expected to lead to slow rates of resistance.
This structural information was used to generate two more potent analogues with favorable physiochemical
properties. In a very preliminary SAR campaign of ~30 compounds, we re-engineered a portion of our lead
scaffold for both synthetic simplicity and stability to provide two analogs that introduce activity beyond Mtb, to
MRSA, E. coli and K. pneumoniae (including a carbapenem-resistant strain), and do not exhibit cytotoxicity to
eukaryotic cells (IC50 >100 µM).
This project will explore and further define critical binding interactions for inhibitors to the bacterial ribosome
that impart selectivity for inhibiting bacterial protein synthesis and broad spectrum antibacterial activity, while
maintaining the lack of mammalian cytotoxicity. Aim 1 will expound on our hypothesis for how compounds can
selectively bind to prokaryotic ribosomes at an undrugged site. If our hypothesis is correct, these inhibitors will
not be active against mammalian ribosomes, thereby mitigating limitations of other ribosome-targeting
antibiotics. Aims 2 and 3 will explore features of related compound families that, based on our hypotheses, are
expected to facilitate more potent inhibition of bacterial ribosomes while maintaining sel...

## Key facts

- **NIH application ID:** 9814101
- **Project number:** 5R01AI127724-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Ryan Edward Looper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-12-21 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814101

## Citation

> US National Institutes of Health, RePORTER application 9814101, Development of Selective Ribosomal P-site Inhibitors (5R01AI127724-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9814101. Licensed CC0.

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