# Exploiting antibiotics to understand the ribosome and translation

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $363,556

## Abstract

The ribosome plays the key role in protein synthesis and is one of the main targets for antibiotics that
inhibit the growth of bacterial cells. Several key aspects of the functions of the ribosome are not fully
understood and antibiotics could play a critical role in gaining insights into unknown facets of translation.
 Our laboratory has been on the forefront of antibiotics research and studies of the functional role of
ribosomal RNA (rRNA). We have elucidated the binding modes and mechanisms of action of a number of
major classes of antibiotics. On the basis of our findings we have proposed the new concept of context- and
protein-specific action of several types of protein synthesis inhibitors. We have also unveiled the operations of
several resistance mechanisms and revealed the principles of regulation of expression of inducible antibiotic
resistance genes. In parallel with our studies of antibiotics, we have advanced the field of ribosome
engineering having constructed the first ribosome with inseparable subunits based on a hybrid of 16S-23S
rRNA, opening new experimental venues for basic research and bioengineering.
 Building upon our expertise in antibiotics, gene regulation and ribosome engineering, we will now
advance these areas to principally new frontiers. Our future research will proceed in three main directions: 1)
We will dedicate our effort to advancing the concept of context-specificity of bacterial ribosomal inhibitors to
become applicable to the eukaryotic ribosome. By using ribosome engineering, structural analysis and
genome-wide tests, we will identify compounds capable of binding in the nascent peptide exit tunnel of the
eukaryotic ribosome and interfering with production of a subset of proteins. 2) Our antibiotic-enforced ribosome
profiling experiments led to an unexpected and exciting finding of internal translation initiation inside a number
of bacterial genes. We will analyze the physiological significance of internal initiation, test the production of the
`alternative' gene products, study the regulation of expression of the genes from two different start codons and
explore the evolutionary penetrance of this phenomenon. 3) The ribosome is believed to have originated in the
pre-protein RNA World. However, all the previous attempts to demonstrate the ability of protein-free rRNA to
catalyze peptide bond formation have been unsuccessful. We will use the synergy between ribosome
engineering and antibiotic studies to generate catalytically active rRNA core. Altogether, the proposed
directions of research should significantly advance the use of antibiotics as medicines and as tools for
exploring ribosome functions in protein synthesis and translation regulation. We will use the knowledge of
antibiotic action to expand our understanding of genome plasticity and gene coding and illuminate the critical
questions of the ribosome origin and evolution.

## Key facts

- **NIH application ID:** 10366000
- **Project number:** 5R35GM127134-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** ALEXANDER S MANKIN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,556
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366000

## Citation

> US National Institutes of Health, RePORTER application 10366000, Exploiting antibiotics to understand the ribosome and translation (5R35GM127134-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366000. Licensed CC0.

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