# RNA modification and antibiotic resistance

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $99,232

## Abstract

ABSTRACT
The application of antibiotics to the treatment of bacterial infections revolutionized modern medical practice. In
the decades since, a combination of improperly controlled usage and the remarkable ability of bacterial
populations to develop resistance to these drugs has severely restricted the clinical usefulness of many
antibiotics. We are now at a critical juncture where the majority of useful antibiotics have known and sometimes
extensive resistance, and few novel replacements or strategies to combat the resistance problem are in active
development. Many clinically useful antibiotics target the bacterial ribosome. One increasingly prevalent form of
resistance to these drugs is alteration of the modification status of the ribosomal RNA (rRNA) via acquired or
intrinsic methyltransferase enzymes. While enzymes responsible for incorporating these antibiotic resistance-
associated rRNA modifications are known, we understand far less about their mechanisms of action (such as
specific substrate recognition), which might offer viable new targets to counter the resistance. Further, we also
currently have a poor understanding of the molecular basis for how rRNA methylation affects ribosome-antibiotic
interactions. The experiments proposed in this application will directly address these critical gaps in our
fundamental knowledge of rRNA methylation and bacterial antibiotic resistance. In the first two aims we will
define the molecular mechanisms of ribosome subunit recognition by two different rRNA modification enzymes,
the acquired aminoglycoside-resistance 16S rRNA (m7G1405) methyltransferases (Aim 1) and the intrinsic
Mycobacterium tuberculosis methyltransferase TlyA (Aim 2). Next, we will develop a new computational and
experimental framework for understanding antibiotic-methylated rRNA interactions (Aim 3). Our goal is to explain
at the molecular level how rRNA modifications limit drug efficacy and how these effects can be evaded.
Collectively, the results of these three independent but complementary aims will deepen our fundamental
understanding of the molecular strategies used by rRNA modification enzymes and the impacts of rRNA
methylation on antibiotic resistance in bacteria. Our results will support future innovative strategies to counter
the resistance conferred by these enzymes, for example, by facilitating the development of inhibitors of m7G1405
methyltransferase activity or 30S substrate binding, and could also lead to the rational design of novel
antimicrobials capable of fully evading the effects of rRNA modification.

## Key facts

- **NIH application ID:** 10818852
- **Project number:** 3R01AI088025-14S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Graeme L Conn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $99,232
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818852

## Citation

> US National Institutes of Health, RePORTER application 10818852, RNA modification and antibiotic resistance (3R01AI088025-14S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10818852. Licensed CC0.

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