Novel ‘Sidekick’ Technique Boosts Antibiotic Effectiveness

Amid a growing incidence of antibiotic-resistant infections and dearth of new drugs to treat them, new strategies are urgently needed to bolster the world’s antibiotic arsenal.

One approach, strongly advocated by a special U.S. Food and Drug Administration task force launched in September, is to develop new antibacterial drugs, but the process can be very costly and time consuming. Rather than endeavor to devise entirely new classes of antibiotics, Professor James J. Collins(BME, MSE, SE) has spent more than five years exploring ways to enhance existing antibiotics to combat bacterial infections more effectively.

Now Collins and researchers in his lab have discovered a new technique designed to render these infections more susceptible to traditional antibiotics. Described in the January 6 online edition of the journal Nature Biotechnology, the technique systematically identifies genes within E. Coli bacteria that inhibit the production of molecules called reactive oxygen species (ROS) that damage the bacteria’s DNA. Once those genes are disabled, the bacteria dramatically increase their production of the DNA-damaging molecules, enabling lower doses of existing antibiotics to kill the more vulnerable bacteria.

Collins’ technique could lead to “sidekick” drugs, to be taken in combination with traditional antibiotics, that disable selected genes and thereby boost ROS production in E. Coli as well as in bacteria that cause tuberculosis, staph infections, salmonella and other diseases.

“We’re showing that engineering approaches can be applied to enhance our existing antibiotics arsenal to take on this growing public health threat,” said Collins.

To find genes that inhibit the production of ROS in E. Coli, the researchers augmented an existing computational model of the metabolic network of the bacterium (consisting of over 4,000 genes) with hundreds of mathematical equations related to ROS production. They next systematically used the model to determine the impact on ROS production of disabling hundreds of different genes in the E. Coli cell.

Collins’ discovery provides, for the first time, a comprehensive, systems-level understanding of the metabolic pathways that produce ROS, thus enabling scientists to pinpoint new gene targets and potential sidekick drugs that enhance antibiotic effectiveness.

“For many biologists, the interest lies in gaining more insight into the underlying processes within the bacteria,” said Collins. “We as engineers are partly interested in these processes but particularly driven to figure out clever ways to utilize existing mechanisms for therapeutic interventions.”

The research team’s next step is to set up a high-throughput, automated process to screen millions of different compounds to identify those that disable ROS-inhibiting genes, and further analyze these compounds to ensure that they’re effective in boosting antibiotic potency without causing side effects or introducing harmful toxins. Meanwhile, a startup company that Collins helped found, EnBiotix, will further develop the technique.

Funded by the National Institutes of Health and Howard Hughes Medical Institute, Collins co-authored theNature Biotechnology paper with CollinsLab researchers Mark P. Brynildsen (now an assistant professor of chemical and biological engineering at Princeton University), Jonathan A Winkler (now a scientist at Seres Health), MD-PhD student Catherine S. Spina (BME) and research assistant Cody MacDonald (BME’12).

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