Researchers have discovered a new stress signaling system that enables bacterial cells to adapt and defend themselves against the immune system and certain antibiotics.
An enzyme, RlmN, was observed to directly detect chemical and stress stress, and rapidly signal for the production of other proteins that allow the bacterial cell to adapt and survive. This breakthrough discovery of RlmN as a stress sensor revealed a new mechanism of antimicrobial resistance that could be a target for drug development.
All living cells have sensors that can detect environmental changes—such as reactive oxygen species (ROS) or free radicals—due to cell stress or metabolism. According to the well-known central dogma of molecular biology, this is achieved using a two-step system consisting of transcription and translation. This means that genes are transcribed into messenger RNAs (mRNA), which are later translated by ribosomes by transfer RNAs (tRNAs) to produce proteins—the functional building blocks of cells.
The latest research from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) of the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, in collaboration with the Singapore Center for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University Singapore and Massachusetts Institute of Technology (MIT),
The discovery of SMART AMR in the RlmN system illustrates that cells have a faster mechanism for cellular responses. This shortcut is the first example of a direct connection between the sensor system and the translation machinery to generate proteins to fight ROS.
In a paper, titled “An RNA modification enzyme directly senses reactive oxygen species for translational regulation in Enterococcus faecalis,” published in Communication in Natureresearchers documented their discovery of RlmN as a stress sensor for ROS in Enterococcus faecalis—a common bacterium found in the human gut that can cause a variety of infections, with catheter-related urinary tract infections being the most prevalent.
They found that when RlmN is inhibited in contact with ROS, it leads to the selective production of resistance proteins and other pathways related to antimicrobial resistance that are known to occur during bacterial responses to stress. Inhibition of RlmN thus represents a signaling mechanism for bacterial drug resistance and immune evasion, as ROS are induced by some antibiotics and human immune cells.
The discovery was made using a sophisticated mass spectrometry technology developed by SMART and MIT to simultaneously identify all 50 different ribonucleic acids (RNA) variants in bacteria. This method allows them to observe changes in cell behavior or pattern mutations that cannot be detected when studied individually.
Using this tool, researchers exposed E. faecalis cells to low, non-toxic doses of various antibiotics and toxic chemicals produced by the immune system. They found that only one of the 50 changes changed—a chemical called 2-methyladenosine (m2A) decreased. As this change is known to be made by RlmN in other better studied bacteria, the SMART AMR researchers confirmed that this, too, is the case in E. faecalis and went on to show how it is inactivated by ROS.
“This is the first time that a direct connection has been found between ROS and RlmN, and it will be a step forward in the development of new treatments for bacterial infections. By understanding how RlmN works and the different ways in which bacteria respond to stress, we can identify other stress sensors that rely on the same mechanisms,” said Professor Peter Dedon, Co-Lead Principal Investigator of SMART and Associate Professor of A MR, MIT.
“Bacteria are highly adaptable and can evolve to resist drugs designed to kill them. This growing resistance is a silent pandemic that poses a global threat to public health because it reduces the effectiveness of existing antibiotics and increases mortality from infections.”
“Therefore, understanding the mechanisms used by bacteria to adapt against stressors will help researchers develop new and novel therapies to combat AMR. Going forward, SMART AMR will work to gain a comprehensive understanding of this new stress response mechanism and possible drug resistance,” said Dr. Lee Wei Lin, Principal Research Scientist at SMART AMR and first author of the paper.
As novel, high-impact solutions to combat AMR are a top priority to improve public health, understanding bacterial stress survival mechanisms is an important step forward for the scientific community. By understanding these cell adaptation and survival mechanisms, researchers will be able to design drugs that inhibit the adaptation response and ensure that pathogens retain their sensitivity to antibiotics.
Wei Lin Lee et al, An RNA modifying enzyme directly senses reactive oxygen species for translational regulation in Enterococcus faecalis, Communication in Nature (2023). DOI: 10.1038/s41467-023-39790-x
Provided by the Singapore-MIT Alliance for Research and Technology
Citation: Researchers discover new bacterial communication system to combat antimicrobial resistance (2023, July 19) retrieved on 22 July 2023 from https://phys.org/news/2023-07-uncover-bacterial-communication-combat-antimicrobial.html
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