Led by Prof. Joanna Trylska and Piotr Chyży from the University of Warsaw's Biomolecular Machines Laboratory, in collaboration with Dr. Marta Kulik from the university's Faculty of Chemistry, and Prof. Yuji Sugita's team from Japan's RIKEN research institute, this international partnership focuses on riboswitches – segments of RNA that control protein production in bacteria.
Their findings, recently published in the prestigious journal Proceedings of the National Academy of Sciences, highlight a novel approach to combating microbial resistance.
The research opens up new avenues for antibiotic development and paves the way for using RNA fragments as a potential strategy in the battle against microbial resistance to antibiotics, Polish state news agency PAP reported.
The researchers hope their methodology will support the drug design process by identifying the most promising compounds for further experimental studies, ultimately contributing to a faster design of RNA segments to combat antibiotic resistance.
Manipulating riboswitches
Riboswitches are fragments of mRNA, which precede the part of mRNA that codes for protein. These RNA segments can switch off protein production when bound by a specific molecule, typically a metabolite.
Thus, manipulating riboswitches could allow for precise control over the production of proteins essential for a cell's survival.
"Naturally occurring riboswitches could be targets for new antibiotics. If we could design molecules that would block a specific riboswitch in pathogenic bacteria, it could lead to the destruction of these cells," explained Trylska. Most known riboswitches occur in bacteria.
The researchers employed advanced molecular dynamics simulations to explore the interaction between riboswitches and antibiotics, utilizing supercomputers, including those at the University of Warsaw.
One aspect of their research involved synthetic riboswitches, which do not occur in all cells, raising the possibility of introducing them into mRNA to control the production of specific proteins.
Designing synthetic riboswitches, however, is challenging due to the need to predict how their structure changes upon binding with their controlling molecule.
"The fact that a molecule binds strongly with a riboswitch doesn't mean it will act as expected in cells," Trylska clarified.
The team's investigation into a synthetic riboswitch that binds with the antibiotic neomycin led to the development of a unique method and tools to understand the entire pathway of drug binding to this RNA segment. Their results could significantly aid in designing synthetic riboswitches and molecules that regulate their dynamics and structure.
"Our work shows how key stages of neomycin's interaction with the riboswitch can be optimized to enhance its regulatory effectiveness in cells," said Trylska.
"The simulation results reveal significant differences in the binding pathway of neomycin to different riboswitch sequences and how these differences affect its activity," she added.
(rt/gs)
Source: PAP, uw.edu.pl