U. CBE study finds new methods to increase antibiotic effectiveness

A study published in Nature Biotechnology this January led by chemical and biological engineering professor Mark Brynildsen has developed new methods to increase the effectiveness of antibiotics in killing harmful bacteria. The findings of this study help address ongoing concerns that bacteria are becoming increasingly resistant to existing antibiotics, a problem Brynildsen called a “public health crisis.”

“Our antibiotic arsenal is still very potent, but the incidence of multi-drug resistant strains continues to increase,” Brynildsen explained. “And at the same time, due to a number of reasons, the number of new antibiotics that are being approved by the FDA continues to decline.”

The research was inspired by previous research done by Boston University biomedical engineering professor and principal investigator Dr. James Collins. Those findings showed that many antibiotics use molecules called reactive oxygen species as part of their mechanisms to kill bacteria. Therefore, the hypothesis of the current study is that there are target proteins in bacteria that inhibit ROS production that could be deactivated to increase ROS production and make bacteria more susceptible to antibiotics.

Brynildsen conducted this research as a postdoctoral fellow at Boston University. His current group at the University researches metabolic models of oxidative stress.

The researchers first created a genome-scale metabolic model to characterize ROS production in E. coli, the first model of its type. They then used the model to predict which target proteins in the bacteria might inhibit ROS production. With these predictions in hand, the group then developed methods to deactivate the targets using chemicals inhibitors.

These treated E. coli were then tested for antibiotic resistance against wild-type counterparts. The group delivered antibiotics to both groups of bacteria and compared how well they withstood the antibiotics course by measuring the colony-forming units, the number of bacteria that can form a colony, left in each group. The results showed that treated E. coli survived at a rate significantly lower than wild-type bacteria.

“We saw that we could boost the efficacy of antibiotics and biocides tenfold to a thousand-fold when we ran the experiments,” Collins said.

Research scholar at the Princeton Environmental Institute Ramanan Laxminarayan, who studies the differences in levels of antibiotic resistance geographically and over time, found promise in the implications of this research.

“This particular study is interesting because there’s been a lot of work on trying to developing new drugs but less so on how to either boost the effectiveness of existing drugs or to combine them with other drugs, which would reduce the likelihood of resistance,” Laxminarayan said.

Collins’ group plans to continue this research by modeling other bacteria, such as Staphylococcus and Mycobacterium tuberculosis. They will also analyze and identify small-molecule inhibitors that deactivate the target proteins.

The group has begun exploring the possibility of bringing this new method to market by using combination therapy, combining a chemical inhibitor with an existing antibiotic. Though the developments are still at an early stage, Collins said he hopes to solidify an option for commercialization within the next year.