How the human species contends with an alarming rise in antibiotic-resistant bacteria is a pressing issue, with some experts predicting these superbugs could kill millions a year by 2050 if we don’t develop new weapons to neutralize the threat. A team of Princeton researchers has put forward a new solution in the form of a first-of-a-kind compound that works like a “poisoned arrow,” penetrating the protective layers of bacteria to tear up its interior, all without succumbing to the regular pitfalls of antibiotic resistance.
The molecule in question goes by the name of SCH-79797, and it was only through years of investigations using a range of classic and cutting-edge imaging and assay techniques that the team uncovered its unique abilities. Through these experiments, it was discovered that the molecule has a two-pronged approach to taking out bacteria, which the researchers liken to a poisoned arrow.
“The arrow has to be sharp to get the poison in, but the poison has to kill on its own, too,” said Benjamin Bratton, molecular biologist and co-first author of the paper.
SCH-79797 fills a significant hole in antibiotics research, which seeks to overcome the two types of bacterial infections that endanger human health, known as Gram-positive and Gram-negative. Gram-negative bacteria feature a robust protective outer layer that repels the advances of most antibiotics, with almost 30 years having passed since a new class of Gram-negative-killing drugs entered the market.
“The thing that can’t be overstated is that antibiotic research has stalled over a period of many decades,” says KC Huang, a professor of bioengineering at Stanford University, who was not a part of the research team. “It’s rare to find a scientific field which is so well studied and yet so in need of a jolt of new energy.”
The Princeton team found that SCH-79797 is able to not only pierce the protective layer of Gram-negative bacteria, it then tears apart the folate within its cells, which it depends on to survive. So far so good, but the team knew that bacteria could very quickly gain the upper hand by breeding new generations and evolving resistance to SCH-79797’s cunning techniques.
So the researchers explored this potential for resistance through “endless” assays and methods, including one known as serial passaging where the bacteria is exposed to the drug over and over. These experiments involved bacterial species known to quickly develop resistance to drugs, such as E. coli, methicillin resistant Staphylococcus aureus and N. gonorrhoeae, with the bacteria offered millions of opportunities to develop resistance to SCH-79797. Still, the team found the molecule to be “irresistible.”
“This is really promising, which is why we call the compound’s derivatives ‘Irresistin,’” says Princeton’s Zemer Gitai, senior author on the paper.
The team was moved to develop these derivatives when the original SCH-79797 presented them with a significant problem. While it killed the bacterial cells with great effectiveness, it acted with similar potency on human cells, which could prove fatal if you to administer it to people. The team addressed this with a derivative called Irresistin-16, which it says is nearly 1,000 times more potent against bacteria than it is against human cells. The scientists were able to use it to cure mice infected with N. gonorrhoeae.
There are hopes that Irresistin-16 itself could not only come to offer a new weapon in the fight against superbugs, but provide a foundation for a new class of drugs that kill them off in novel ways.
“This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance,” says Gitai. “From a ‘Why it’s useful’ perspective, that’s the crux. But what we’re most excited about as scientists is something we’ve discovered about how this antibiotic works – attacking via two different mechanisms within one molecule – that we are hoping is generalizable, leading to better antibiotics – and new types of antibiotics – in the future.”
The research was published in the journal Cell.
Source: Princeton University
