A new web tool Accelerate drug discovery to kill Gram negative bacteria, which are responsible for the overwhelming majority of antibiotic-resistant infections and deaths, according to new research published by the journal Nature Microbiology.
The tool too offers information about chemical changes Discreet that can convert drugs that kill other bacteria into drugs to fight gram-negative infections.
The team demonstrated that the system works by modifying a Gram-positive drug and testing it against three bacterial responsible Gram-negative different from mouse sepsis. The drug was successful against each of them.
"It is really difficult to find new antibiotics for Gram-negative pathogens, because you are bacteria have an extra membrane, an outer membrane, which is very good for keeping antibiotics out, "explains the University of Illinois chemistry professor Paul Hergenrother, who led the research.
The challenge is so great that the FDA has not approved new classes of medications to fight Gram negative bacteria in 50 years, says Hergenrother. "A few years ago, we discovered the molecular characteristics that allowed an antibiotic compound to overcome this barrier," he explains. "Now, we have developed a tool to help others do this too."
Evaluate the pharmacological compounds
The new application, called eNTRyway ' may quickly evaluate pharmacological compounds potential to determine if they have the molecular characteristics that will allow them to cross the membrane and accumulate within Gram-negative bacteria.
Developed by graduate student Bryon Drown, the app can also point out ways to modify existing drugs, for example, those that work against Gram-positive bacteria, to turn them into potent killers of Gram-negative pathogens.
As a demonstration of this latter capacity, the postdoctoral researcher and author co-author of the study, Erica Parker, used the tool to identify a drug that is already in use against Gram-positive infections that, with a basic chemical modification, They could potentially develop to fight Gram-negative bacteria.
By adding a positively charged chemical group known as an amine to the drug, Parker created a compound that, as other tests revealed, accumulated in Gram-negative bacteria and was effective against several types of Gram-negative infections in mice. The process of identifying the compound and modifying it it took only a few weeks, adds Hergenrother.
"We must bear in mind that before this they had occurred more than 100 derivatives of this same compound. We find them in patents and documents, he remembers. And none of these other derivatives had a notable Gram-negative activity. "
Hergenrother and his colleagues have identified so far more than 60 antibiotics that are effective only against Gram-positive bacteria but that can become medicines to fight Gram-negative infections. These compounds kill bacteria in a variety of different ways. The newly created drug, known as Debio-1452-NH3, interferes with the synthesis of fatty acids in bacterial cells, but not in mammals.
Hergenrother adds that the new tool will speed up the process of drug discovery to combat the growing problem of antibiotic resistant infections. "We can use this tool to quickly identify compounds that accumulate in Gram-negative bacteria," he says.