Characterizing riboswitches in methicillin-resistant staphylococcus aureus as potential antibiotic targets

The National Institute of Allergy and Infectious Diseases awarded $151,760 to the Regents of the University of Michigan on December 14, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support postdoctoral research characterizing riboswitches in methicillin-resistant Staphylococcus aureus as potential antibiotic targets.

The fellowship provides advanced, multidisciplinary training in RNA biology, structural biochemistry, and single-molecule fluorescence microscopy. The research investigates bacterial gene regulation by riboswitches—structured RNA elements that regulate gene expression by sensing cellular metabolites—to inform development of novel antibiotics. Riboswitches are ubiquitous in pathogens yet absent in humans, making them attractive antimicrobial targets. The work focuses on two functionally distinct MRSA riboswitches: the FMN riboswitch, a translational repressor, and the MN2 riboswitch, a translational activator. The postdoctoral researcher will employ single-molecule fluorescence assays, cryo-electron microscopy, and computational modeling to elucidate how ligand binding modulates riboswitch-mediated gene regulation and how riboswitches regulate transcriptional and translational processes.

The award period runs from December 14, 2026, through June 30, 2029, with performance at Ann Arbor, Michigan.

Abstract

Designed to provide the applicant with advanced, multidisciplinary training at the intersection of RNA biology, structural biochemistry, and single molecule fluorescence microscopy, this postdoctoral fellowship proposal aims to investigate bacterial gene regulation by riboswitches to inform the development of novel antibiotics. Riboswitches are structured RNA elements that regulate bacterial gene expression by sensing cellular metabolites and modulating transcription or translation. These regulatory rnas are ubiquitous in pathogens yet absent in humans, making them attractive targets for antimicrobial strategies. Among clinically important pathogens, methicillin-resistant staphylococcus aureus (MRSA) uses riboswitches to regulate essential genes involved in cofactor metabolism and metal ION homeostasis. Despite their biological importance, the dynamic mechanisms by which riboswitches influence transcriptional pausing and translation initiation remain incompletely understood. In this proposal, I will use a combination of single-molecule fluorescence assays, CRYO-electron microscopy (CRYO-EM), and computational modeling to dissect the mechanisms of two functionally distinct MRSA riboswitches: the FMN riboswitch, a translational repressor, and the MN²⁺ riboswitch, a translational activator. Recent work from the sponsor lab has uncovered that riboswitches can regulate transcription by influencing RNA polymerase (RNAP) active site dynamics and RNA exit channel interactions, sometimes in cooperation with the 30S ribosomal subunit. This work has opened the door to a new understanding of riboswitch-mediated gene regulation as a multi-component RNA-protein interaction. My proposal focuses on three specific aims:  aim 1: define how ligand binding modulates riboswitch-mediated gene regulation in MRSA.  aim 2: elucidate riboswitch-regulated transcriptional and translational dynamics using single-molecule approaches.  aim 3: reveal structural interfaces of riboswitch-RNAP-ribosome complexes via single-particle CRYO- electron microscopy (CRYO-EM) and computational modeling. These studies will provide critical insight into riboswitch mechanism, build my expertise in high-resolution biophysical methods, and contribute to foundational knowledge that may inform future antimicrobial strategies. The proposed research will support my long-term goal of leading an academic lab focused on RNA-mediated gene regulation and its therapeutic potential.