Princeton research team finds ‘poison arrow’ molecule to “smash” superbugs from the inside

How humans respond to the alarming growth of antibiotic-resistant bacteria is a pressing question, and some experts predict that if we don’t develop new weapons to eliminate the threat, these superbugs could kill millions of people each year by 2050. A team of researchers at Princeton University has come up with a new solution that works like a “poison arrow” that penetrates the protective layer of bacteria and rips apart the inside of a bacterium, all of which does not succumb to the “conventional trap” of antibiotic resistance.

The molecule, called SCH-7979797, was discovered by the team after years of research using a range of classic cutting-edge imaging and detection techniques. Through these experiments, the researchers found that the molecule has a two-pronged effect and can also be used as a “poison arrow” to destroy bacteria.

Benjamin Bratton, a molecular biologist and lead author of the paper, said: “To get poison in, the arrow needs to be sharp enough, but the poison has to kill the bacteria on its own.” “

SCH-797977 fills an important gap in antibiotic research that seeks to overcome two types of bacterial infections that are harmful to human health, known as Gram-positive and gram-negative. Gram-negative bacteria are characterized by a solid protective layer that can repel most antibiotics, nearly 30 years since a new class of Gram-negative anti-killer drugs entered the market.

“There’s no denying that antibiotic research has stagnated for decades,” said KC Huang, a professor of bioengineering at Stanford University who is not part of the research team. “It’s rare to find that research in a scientific field is so deep, but it’s so much to breathe new life into it. “

The Princeton team found that SCH-7979797 not only pierced the protective layer of gram-negative bacteria and then tore open the folic acid in its cells, which is the basis on which it lives. So far so good, but the team knows that bacteria can quickly gain the upper hand by breeding a new generation and evolving resistance to the cunning technique of THE SCH-7979797.

So the researchers explored this potential resistance through a number of experiments and methods, including an experiment called “concatenation transmission”, in which bacteria are exposed to drugs again and again. The types of bacteria involved in these experiments are known to develop rapid resistance to bacteria such as E. coli, Methicillin-resistant Staphylococcus aureus and gonorrhoea, which provide millions of opportunities to develop resistance to SCH-79797. Still, the team found the molecule “irresistible.”

“It’s really promising, and that’s why we call the derivative of this compound ‘Irresistin,'” said Zemer Gitai of Princeton University, a senior author of the paper.

When the original SCH-7979797 asked them a major problem, the team was moved to develop these derivatives. Although it kills bacterial cells well, it has a similar effect on human cells, which can prove fatal if administered. The team solved the problem with a derivative called Irresistin-16, which it says is nearly 1,000 times more lethal to bacteria than to human cells. Scientists were able to use it to treat mice infected with gonorrhoea.

It is hoped that the Irresistin-16 itself will not only provide a new weapon against superbugs, but also provide the basis for a new class of drugs to kill them in novel ways.

“This is the first antibiotic that can target gram-positive and gram-negative bacteria without resistance. Gitai said. “From the ‘why it’s useful’, that’s the key. But what we’re most excited about as scientists is that we’ve discovered something about how this antibiotic works — by attacking it through two different mechanisms within a molecule — and we hope that it will be common to develop better antibiotics in the future — and new antibiotics. “

The study was published in the journal Cell.