Breakthrough stress sensor discovery reveals recent mechanism of antimicrobial resistance

Researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, in collaboration with Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University Singapore (NTU Singapore) and Massachusetts Institute of Technology (MIT), have discovered a brand new stress signaling system that allows bacteria cells to adapt and protect themselves against the immune system and certain antibiotics. An enzyme, RlmN, was observed to directly sense chemical and environmental stresses, and rapidly signal for the production of other proteins that allow the bacteria cell to adapt and survive. This breakthrough discovery of RlmN as a stress sensor has revealed a brand new mechanism of antimicrobial resistance that could be targeted for drug development.

All living cells have sensors that detect environmental changes – comparable to reactive oxygen species (ROS) or free radicals – attributable to cell stress or metabolism. In accordance with the well-known central dogma of molecular biology, that is achieved using a two-step system comprising transcription and translation. Which means genes are transcribed into messenger RNAs (mRNA), that are subsequently translated on ribosomes by transfer RNAs (tRNAs) to supply proteins – the functional constructing blocks of cells.

SMART AMR’s discovery of the RlmN system illustrates that cells possess a much quicker mechanism for cell responses. This shortcut is the primary example of a direct connection between a sensor system and translation machinery to generate proteins to combat ROS.

In a paper titled “An RNA modification enzyme directly senses reactive oxygen species for translational regulation in Enterococcus faecalis”, published within the scientific journal Nature Communications. The researchers document their discovery of RlmN as a stress sensor for ROS in Enterococcus faecalis (E. faecalis) – a typical bacteria present in the human gut that could cause quite a lot of infections, with catheter-associated urinary tract infections being probably the most prevalent. They found that when RlmN is suppressed upon contact with ROS, it results in the selective production of resistance proteins and other pathways related to antimicrobial resistance known to occur during bacterial responses to emphasize. RlmN inhibition thus represents a signaling mechanism for bacterial drug resistance and immune evasion, since ROS is induced by certain antibiotics and human immune cells.

The invention was made using a complicated mass spectrometry technology developed at SMART and MIT to concurrently discover all 50 different Ribonucleic acids (RNA) modifications in bacteria. This approach allowed them to watch changes in cell behavior or pattern mutations that can’t be detected when studied individually.

Using this tool, the researchers exposed E. faecalis cells to low, non-toxic doses of assorted antibiotics and toxic chemicals made by the immune system. They found that only considered one of the 50 modifications modified – a chemical called 2-methyladenosine (m2A) decreased. As this modification was known to be made by RlmN in other better-studied bacteria, SMART AMR researchers proved that this too, was the case in E. faecalis and went on to indicate the way it is inactivated by ROS.

That is the primary time a direct connection has been found between ROS and RlmN, and it might be a step forward in developing recent treatments for bacterial infections. By understanding how RlmN works and the several ways wherein bacteria respond to emphasize, we could uncover other stress sensors that depend on similar mechanisms.”

Professor Peter Dedon, Co-Lead Principal Investigator at SMART AMR, MIT Professor and Co-Corresponding Creator of the Paper

“Bacteria are incredibly adaptable and might evolve to withstand drugs designed to kill them. This growing resistance is a silent pandemic that poses a world threat to public health because it reduces the efficacy of existing antibiotics and increases mortality rates from infections. Thus, understanding the mechanisms bacteria utilize to adapt against stressors helps researchers develop recent and novel therapies to combat AMR. Moving forward, SMART AMR will work on gaining a comprehensive understanding of this recent mechanism of stress response and possible drug resistance,” said Dr Lee Wei Lin, Principal Research Scientist at SMART AMR and first writer of the paper.

As novel, high-impact solutions to combating AMR are a top priority to enhance public health, understanding bacterial stress survival mechanisms is a vital step forward for the scientific community. By understanding these cell adaptation and survival mechanisms, researchers can design drugs that prevent the variation response and make sure that the pathogens retain their sensitivity to antibiotics.

The research is carried out by SMART and supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) program.