Biotechnology

Bacterial communication systems can help address AMR

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The novel stress signaling system allows bacterial cells to adapt and protect themselves from the immune system and certain antibiotics.

The discovery was made by researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at the Singapore-MIT Alliance for Research and Technology (SMART), an MIT research firm in Singapore, in collaboration with the Singapore Center for Environmental Life Sciences Engineering (SCELSE) , Singapore’s Nanyang Technological University (NTU Singapore) and the Massachusetts Institute of Technology (MIT).

The enzyme, RlmN, was observed to directly sense chemical and environmental stress, and quickly signal for the production of other proteins that allow bacterial cells to adapt and survive. This breakthrough discovery of RlmN as a stress sensor has revealed a novel mechanism of antimicrobial resistance that can be targeted for drug development.

All living cells have sensors that detect changes in the environment – ​​such as reactive oxygen species (ROS) or free radicals – caused by 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 RNA (mRNA), which is then translated on the ribosome by transfer RNA (tRNA) to produce proteins – the functional building blocks of cells.

SMART AMR’s discovery of the RlmN system illustrates that cells have a much more rapid cell response mechanism. This shortcut is the first example of a direct link between sensor systems and translation machinery to generate proteins to fight ROS.

In a paper, “RNA modification enzymes directly sense reactive oxygen species for translational regulation in Enterococcus faecalis,” published in the scientific journal Nature Communications, the researchers document their discovery of RlmN as a stress sensor for ROS in Enterococcus faecalis. E. faecalis is a common bacterium found in the human intestine that can cause a variety of infections, with urinary tract infections being the most common.

They found that when RlmN is suppressed on contact with ROS, it leads to the production of selective resistance proteins and other pathways associated with antimicrobial resistance that are known to occur during bacterial responses to stress. RlmN inhibition represents a signaling mechanism for bacterial drug resistance and immune evasion, as ROS are induced by certain antibiotics and human immune cells.

The discovery was made using mass spectrometry technology developed at SMART and MIT to simultaneously identify 50 different ribonucleic acid (RNA) modifications in bacteria. This approach allowed them to observe changes in cell behavior or pattern mutations that could not be detected when studied individually.

Disabled by ROS

Using this tool, the researchers were exposed E. faecalis cells to low, non-toxic doses of various antibiotics and toxic chemicals made by the immune system. They found that only one of the 50 modifications changed – a chemical called 2-methyladenosine (m2A) decreased. Because this modification is known to be carried out by RlmN in other, better studied bacteria, the SMART AMR researchers proved that it also occurs in E. faecalis and went on to show how it was disabled by ROS.

“This is the first time that a direct association has been found between ROS and RlmN, and this may be a step forward in developing a new treatment for bacterial infections. By understanding how RlmN works and the different ways bacteria respond to stress, we can uncover other stress sensors that depend on similar mechanisms,” said Peter Dedon, co-principal investigator in SMART AMR, MIT professor and corresponding author. from paper.

“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 by reducing the efficacy of existing antibiotics and increasing mortality from infection. Thus, understanding the mechanisms by which bacteria adapt against stressors is helping researchers develop new and new therapies to combat AMR. Going forward, SMART AMR will work to gain a comprehensive understanding of this new mechanism of stress response and possible drug resistance,” said 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 for improving public health, understanding the mechanisms of survival of bacterial stress is an important step forward for the scientific community.

The researchers say that by understanding these mechanisms of cell adaptation and survival, it is possible to design drugs that prevent the adaptive response and ensure that pathogens retain their sensitivity to antibiotics.

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