One of the most significant challenges that constitutes a risk to the health of humans is antibiotic resistance. As a result, a great number of investigations have been carried out on the problem, and several researchers all over the world are working toward the common goal of putting an end to the catastrophe that claims the lives of over a million people every year.
Researchers from Rockefeller University have developed a new antibiotic with the assistance of computer models of the gene products produced by bacteria. It was found that it could kill bacteria that were resistant to other antibiotics. It has been demonstrated that the chemical known as cilagicin is effective against MRSA, C. diff, and a number of other potentially lethal infections through a novel method.
According to Sean F. Brady, the Evnin Professor and the corresponding author of the paper, in a news statement that was published by the school, “This isn’t just a cool new chemical, it’s a validation of a fresh strategy to drug development.” [Citation needed] This research is a prime illustration of how computational biology, genomic sequencing, and synthetic chemistry may work in concert to reveal previously unknown aspects of bacterial evolution.
bacteria fighting and killing each other
It should come as no surprise that the majority of antibiotics are derived from bacteria, as the process of bacterial evolution consists of the bacteria coming up with novel ways to eliminate one another. However, the development of resistance in bacteria also contributes to the formation of problems such as antibiotic-resistant bacteria, which has resulted in the requirement for the development of new active chemicals.
However, the genomes of resistant bacteria, which are notoriously difficult or even impossible to study in a laboratory, almost certainly include many antibiotics that have not yet been discovered. “Many antibiotics are derived from bacteria, but the majority of bacteria cannot be cultivated in the laboratory,” adds Brady. Therefore, it stands to reason that the vast majority of antibiotics are unavailable to us.
Since the beginning of the 2000s, Brady’s research group has been using an alternative strategy, which entails searching for antibacterial genes in soil and cultivating them inside bacteria that are more amenable to lab conditions. However, this strategy does not come without its own set of constraints. The majority of antibiotics are thought to have originated from the genetic sequences that are a part of what are known as biosynthetic gene clusters. These gene clusters are groupings of genes that work together to code for multiple proteins together. But with the technology that is available today, those clusters are typically unavailable.
Brady and his colleagues turned to algorithms after they were unable to unlock numerous gene groups found in bacteria. By dissecting the genetic instructions included in a DNA sequence, today’s algorithms are able to make educated guesses about the composition of the antibiotic-like compounds that a bacteria carrying these sequences would be likely to produce. And then, organic chemists can utilize the data to synthesis the anticipated structure in the laboratory using the materials that they have available.
A chemical with potential
Postdoctoral colleagues from the Brady lab, Zonggiang Wang and Bimal Koirala, began their research by working on a massive genetic-sequence database. Their objective was to locate potential bacterial genes that were not previously investigated but were thought to be important in killing other bacteria. The “cil” gene cluster stood out due to its close proximity to other genes that are utilized in the manufacturing of antibiotics. Research on this gene cluster had not been done previously in this context. After that, the researchers followed protocol and inputted its important sequences into an algorithm, which then offered a few molecules that “cil” most likely creates. A substance known as cilagicin, which was found to be an efficient antibiotic, was the chemical in question.
It was discovered that the action of Cilagicin is achieved through the interaction of two molecules known as C55-P and C55-PP, both of which are essential to the maintenance of the cell walls of bacteria. It is common for bacteria to evolve resistance to the antibiotics that are currently available by piecing together a cell wall using the leftover component. Drugs such as bacitracin only bind to one of those two molecules at a time; they cannot do so with both. Therefore, the group has a hunch that the capability of cilagicin to halt the activity of both molecules may in fact constitute an obstacle that cannot be overcome and thus prevents resistance.
Even though cilagicin has not yet been tested on humans, the Brady lab plans to carry out additional syntheses to enhance the compound for use in subsequent studies. Additionally, they will test it in animal models against a wider variety of infections to determine which conditions it would be most effective in treating.