Discovery of a unique bacterial communication system may help to tackle antibiotic resistance – Study
Researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, in collaboration with the Nanyang Technological University of Singapore (NTU Singapore), the Singapore Centre for Environmental Life Sciences Engineering (SCELSE), and Massachusetts Institute of Technology (MIT), have discovered a new stress signaling system that enables bacteria cells to adapt and protect themselves against the immune system and certain antibiotics. SMART has conducted National Research Foundation (NRF)-supported study .
RImN, an enzyme, 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. The discovery of RlmN as a stress sensor has revealed a new antimicrobial resistance mechanism that can be targeted for medication development.
All living cells have sensors that detect environmental changes induced by cell stress or metabolism, such as reactive oxygen species (ROS) or free radicals. This occurs through a two-step system comprised of transcription and translation. It means that genes are transcribed into messenger RNAs (mRNA), which are then translated by transfer RNAs (tRNAs) on ribosomes to make proteins – the functional building blocks of cells.
The discovery of the RlmN system by SMART AMR shows that cells have a significantly faster mechanism for cell responses. This is the first example of a direct link between a sensor system and translation machinery to produce proteins to resist ROS.
The researchers documented their discovery of RlmN as a stress sensor for ROS in Enterococcus faecalis (E. faecalis) – a common bacteria found in the human gut that can cause a variety of infections, with catheter-associated urinary tract infections being the most common – in a paper titled “An RNA modification enzyme directly senses reactive oxygen species for translational regulation in Enterococcus faecalis”, published in the scientific journal Nature Communications.
RlmN inhibition thus represents a signaling mechanism for bacterial drug resistance and immunological evasion, because ROS is generated by some drugs and human immune cells.
The discovery was made utilizing a powerful mass spectrometry method developed by SMART and MIT to identify all 50 distinct RNA alterations in bacteria at the same time. This method enabled them to spot changes in cell behavior or pattern mutations that would have been impossible to notice in individual studies.
Using this method, the researchers exposed E. faecalis cells to mild, non-lethal doses of antibiotics and harmful substances produced by the immune system. They discovered that only one of the 50 alterations changed – a molecule known as 2-methyladenosine (m2A) reduced. Because this alteration was known to be generated by RlmN in other better-studied bacteria, SMART AMR researchers demonstrated that it was also the case in E. faecalis and demonstrated how it is inactivated by ROS.
By understanding how RlmN works and the different ways in which bacteria respond to stress, we could uncover other stress sensors that rely on similar mechanisms, according to Professor Peter Dedon, Co-Lead Principal Investigator at SMART AMR, MIT Professor and co-corresponding author of the paper.
Moving forward, SMART AMR will work on gaining a comprehensive understanding of this new mechanism of stress response and possible drug resistance, commented Dr Lee Wei Lin, Principal Research Scientist at SMART AMR and first author of the paper.
By understanding these cell adaptation and survival mechanisms, researchers can design drugs that prevent the adaptation response and ensure that the pathogens retain their sensitivity to antibiotics.
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