A new web tool speeds the discovery of drugs to kill Gram-negative bacteria, which are responsible for the vast majority of antibiotic-resistant infections and deaths. The tool also offers insights into discrete chemical changes that can convert drugs that kill other bacteria into drugs to fight Gram-negative infections. The team proved the system works by modifying a Gram-positive drug and testing it against three different Gram-negative bacterial culprits in mouse sepsis. The drug was successful against each.
Researchers reported their findings in the journal Nature Microbiology.
“It’s really hard to find new antibiotics for Gram-negative pathogens, because these bacteria have an extra membrane, an outer membrane, that’s very good at keeping antibiotics out,” said University of Illinois chemistry professor Paul Hergenrother, who led the research.
The challenge is so profound that no new classes of drugs to fight Gram-negative bacteria have been approved by the Food and Drug Administration in 50 years, Hergenrother said.
“A few years ago, we discovered the molecular features that allowed an antibiotic compound to surpass this barrier,” he said. “Now, we’ve developed a tool to help others do this as well.”
The new app, called eNTRyway, can quickly evaluate potential drug compounds to determine if they have the molecular characteristics that will enable them to cross the membrane and accumulate inside Gram-negative bacteria.
Developed by graduate student Bryon Drown, the app also can point to ways of modifying existing drugs – for example, those known to work against Gram-positive bacteria – to convert them into potent killers of Gram-negative pathogens.