New approach identifies sidekick drug to help antibiotics defeat infections
Researchers from Boston University have developed a new approach to attack bacterial infections, by making them more susceptible to traditional antibiotics. The novel technique could allow scientists to identify sidekick drugs that spur bacteria to increase their production of compounds that damage their own DNA, thus making it easier for conventional therapies to deal the fatal blow.
The strategy, described Sunday in the journal Nature Biotechnology, could offer a powerful approach to fighting an increasing number of resistant infections, which has become a national priority. In September, the US Food and Drug Administration, which approves new drugs, created a special task force to help guide and spur the develpoment of new antibacterial drugs, noting that more than 70 percent of the bacteria behind infections contracted in hospitals are resistant to at least one commonly-used antibiotic, and that the number of new antibiotics has dropped off since the 1980s.
Instead of focusing on the tricky business of coming up with whole new classes of antibiotics, however, the Boston University team looked at ways of enhancing the existing drug arsenal.
“It’s in the spirit of, ‘Look, we’ve got pretty good antibiotics—can we find ways to extend their shelf lives and make them better?’ ” said James J. Collins, a BU biomedical engineer who led the work. His laboratory has in recent years focused on novel ways to increase the power of antibiotics against infections.
In the new study, researchers examined a vast flow chart of the metabolism of E. coli to understand how the bacteria naturally create compounds, called reactive oxygen species, that damage the fundamental building blocks of a cell, such as DNA and proteins. They looked for and found genes that reduce production of the harmful compounds. Blocking those genes could have the opposite effect, increasing the amount of reactive oxygen species. When they deleted those genes and treated the bacteria with traditional antibiotics, the combination approach made the antibiotics markedly more effective at killing bacteria.
Of course, if such an approach were ever to make its way outside a laboratory dish, scientists would need a way to emulate their controlled genetic manipulation in a person’s body. To prove that was theoretically possible, they used a toxic fungicide called carboxin that could knock out one of the genetic targets they had pinpointed, in combination with the antibiotic, ampicillin. As predicted, it was a potent combination.
Collins said he would never suggest using that particular toxic chemical therapeutically, but that his team would now use their technique to screen chemical libraries and search for compounds that could hit some of the targets of interest they had identified without causing side effects.
The technique will be further developed, Collins said, by a startup company he helped found, called EnBiotix, and it has attracted some interest from pharmaceutical companies. In his own laboratory, Collins hopes to extend the technique to understand ways to increase the vulnerability of other bacteria, such as those that cause staph infections, an infection that commonly afflicts people with cystic fibrosis, and tuberculosis.