Many frontline antibiotics are no longer useful against some bacterial infections, which are increasingly gaining resistance to drugs and sharing that resistance with other bacteria. Experts have warned that antibiotic resistant infections pose a major threat to public health. But scientists have now developed a new method for identifying molecular combinations that could make them more effective against antibiotic resistant pathogens. This new kind of drug pipeline was used to screen over one million interactions between small molecules and antibiotics, and bacteria. This effort, which was reported in the Proceedings of the National Acedemy of Sciences (PNAS), identified a small molecule that made rifampin, an antibiotic, more effective.
Molecules known as adjuvants can make bacteria more vulnerable to antibiotics.
“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said co-first study author Megan Tse.
The investigators were aiming to identify treatments for the ESKAPE pathogens, which the World Health Organization has prioritized as threats. The researchers focused on the ESKAPE pathogens Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa in this study.
Assessing the efficacy of millions of different combinations of antibiotics and small molecules against three bacterial pathogens is no small order. The research team used a recently developed tool known as DropArray; it utilizes hundreds of thousands of tiny wells, and each well contains little mixtures of droplets that contain bacteria and molecules. Each combination is tagged with a fluorescent barcode so they can be easily identified.
The scientists tracked bacterial growth in every well, to find wells where the bacteria could not grow; these wells would contain the chemical combinations that could kill bacteria.
After testing over 1.3 million combinations in one month, the investigators found a molecule now known as P2-56 that increased the efficacy of multiple antibiotics against A. baumannii and K. pneumoniae.
The researchers also made changes to increase the potency, and created P2-56-3. It can make rifampin much more effective.
More research will be necessary before we know if this molecular combination will be safe and effective in people, but this approach shows that we might be able to use some existing tools in the fight against antibiotic resistant infections.
“We’ve shown that with this technology and throughput, combination screening is a doable thing,” said co-senior study author Paul Blainey, core member of the Broad and a professor at MIT. “I hope this expands people’s imaginations of what can be done.”
Sources: Broad Institute of MIT and Harvard, Proceedings of the National Academy of Sciences (PNAS)
