Healthcare, India (Commonwealth Union) – Food-borne diseases such as typhoid, caused by Salmonella Typhimurium, pose a severe threat to public health, particularly in India. The indiscriminate use of antibiotics has led to the development of antibiotic-resistant strains of this bacterium, making infections increasingly difficult to treat.
Antibiotic-resistant strains of bacteria are becoming a major concern for global health. The overuse and misuse of antibiotics have led to the evolution of bacteria that are resistant to these life-saving drugs. This phenomenon is not limited to a specific region or nation; it is a worldwide issue that threatens the effectiveness of medical treatments and the overall health of the population. The emergence of antibiotic-resistant strains is a direct result of the widespread use of antibiotics in various sectors, including human medicine, veterinary medicine, and agriculture. When antibiotics are used excessively, it allows for the survival and proliferation of bacteria that have developed resistance. These resistant strains can then spread to other individuals, leading to the rapid dissemination of antibiotic resistance across populations.
Dipshikha Chakravortty, Professor in the Department of Microbiology and Cell Biology (MCB) at the Indian Institute of Science (IISc) indicated that the strategy of salmonella to survive are par excellence. With the rise in antimicrobial resistance in Salmonella, it is not impossible to eliminate.
In a recent study that appeared in Redox Biology, Chakravortty and her team identified the way the bacterium uses a key molecule known as spermidine to protect itself from the host’s immune defenses. They also discovered that an existing FDA-approved drug is able to inhibit spermidine production, thereby reducing the bacterium’s ability to cause infection.
Spermidine is a naturally occurring polyamine that plays a crucial role in various biological processes. Found in all living organisms, spermidine is involved in cellular growth, differentiation, and survival.
Researchers of the pointed out that when Salmonella infects a host, it is engulfed by macrophages, a type of immune cell. In response, macrophages increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), creating a hostile environment intended to eliminate the bacteria.
Researchers of the study revealed that Salmonella, a bacterium, heavily relies on a polyamine known as spermidine. It not only generates its own spermidine but also seizes the host’s machinery to produce additional amounts. During the recent study, researchers discovered that spermidine is essential for Salmonella to safeguard itself from oxidative stress within macrophages. Spermidine specifically controls the expression of an enzyme called GspSA, which facilitates spermidine’s robust binding to a protein named Glutathionyl (GSH). This conjugate produces chemical bonds with various bacterial proteins, fortifying and protecting them during oxidative stress. Mice infected with Salmonella mutants lacking the ability to import and synthesize spermidine exhibited higher survival rates when contrasted to those infected with normal Salmonella.
“Spermidine from both bacteria and the host acts like a robust weapon for Salmonella to safeguard against reactive oxygen species,” said Chakravortty.
Upon discovering this, the team started searching for medications capable of diminishing spermidine levels within the host. They honed in on D, L-alpha-difluoromethylornithine (DFMO), an FDA-approved drug commonly utilized for treating human African trypanosomiasis. It was observed that DFMO permanently obstructs ornithine decarboxylase, an enzyme crucial to a fundamental stage of the spermidine biosynthesis pathway within the host, thereby lowering its levels and rendering the bacteria more susceptible. In mice treated with this drug, survival rates were notably improved.
The targeting of specific enzymes has been key in recent times for treating medical conditions, hence enzyme research has been a significant area of interest for researchers.
“Since we are targeting the host machinery, and not targeting the bacteria, it will not evolve genetically,” said Abhilash Vijay Nair, who is a former PhD student at MCB and the 1st author of the paper.
DFMO also engages an enzyme known as arginase, which is responsible for the availability of the amino acid arginine for spermidine synthesis. When arginase is blocked, the production of spermidine decreases, making bacteria more vulnerable to oxidative stress. Consequently, DFMO holds promise as a potential treatment for salmonellosis, according to the researchers. In future studies, they aim to identify other factors that may be involved in regulating spermidine synthesis.
With the growing need for new treatments to combat antimicrobial resistance, this study be among the key solutions in resolving drug resistance.
