Researchers at the Indian Institute of Science (IISc) have discovered that Salmonella Typhimurium, a bacterium causing food-borne diseases like typhoid, uses a molecule called spermidine to protect itself from the host’s immune response. Scientists say that by targeting spermidine production through a drug can weaken the Salmonella’s defences, making it more susceptible to the host’s immune system. The researchers explain that the indiscriminate use of antibiotics over the years has allowed this bacterium to become resistant, posing a major hurdle in treating infections.
“Salmonella’s strategies to survive are par excellence. With an increase in antimicrobial resistance in Salmonella, it is just impossible to eradicate,” says Dipshikha Chakravortty, Professor in the Department of Microbiology and Cell Biology (MCB), IISc.
In a recent study published in Redox Biology, the IISc team showed how the bacterium uses the molecule spermidine to shield itself from the onslaught of the host’s defence machinery. An existing FDA-approved drug called D, L-alpha-difluoromethylornithine (DFMO), used widely for treating human African trypanosomiasis can reduce spermidine production, weakening the bacterium’s ability to cause infection.
“When Salmonella infects a host, it is engulfed by macrophages– cells that are part of the host’s immune system. After engulfment, macrophages start increasing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) inside themselves. This creates a hostile environment for the bacteria to survive,” reads an IISc statement.
Researchers tested on mice with mutant Salmonella lacking the ability to import and produce spermidine showed higher survival rates compared to the ones infected with normal Salmonella. Spermidine from both bacteria and the host acts like a robust weapon for Salmonella to safeguard against reactive oxygen species.
Study found that DFMO irreversibly blocks ornithine decarboxylase–an enzyme involved in a key step of the spermidine biosynthesis pathway in the host, reducing its levels and making the bacteria more vulnerable. “Since we are targeting the host machinery, and not targeting the bacteria, it will not evolve genetically,” says Abhilash Vijay Nair, a former PhD student at MCB, and the first author of the paper.
DFMO also acts on another enzyme called arginase, which is responsible for ensuring that an amino acid called arginine is available for spermidine synthesis. When arginase is blocked, less spermidine is synthesised, again making the bacteria more susceptible to oxidative stress. Researchers believe the drug is a promising candidate for treating salmonellosis and in future studies, they will aim to find other players that might be involved in controlling spermidine synthesis.