Researchers from the Emory Antibiotic Resistance Center at Emory University School of Medicine in Atlanta, GA, suggest that old antibiotics may be repurposed to fight superbugs.

The study focuses on a type of resistance called heteroresistance, which occurs when only a subpopulation of bacteria within a larger population becomes resistant to an antibiotic, while the rest remain susceptible. Heteroresistance can be difficult to detect in standard laboratory tests because the resistant bacteria revert to a small proportion once the antibiotic is removed.

“We can think of heteroresistance as bacteria that are half resistant,” explains study co-author David Weiss, Ph.D. “That’s why they are hard to see in the tests that hospitals usually use.”

Identifying heteroresistance could allow doctors to select antibiotic combinations that target different subpopulations within a bacterial culture. Laboratory experiments and mouse model studies, reported in Nature Microbiology, suggest this strategy may help overcome infections with difficult-to-treat, antibiotic-resistant bacteria.

In their study, the team analyzed 104 bacterial samples obtained through the CDC’s Multi-site Gram-negative Surveillance Initiative, focusing on carbapenem-resistant Enterobacteriaceae. Over 85% of the isolates were resistant to at least two different antibiotics.

The researchers discovered that combining the antibiotics to which a bacterial population was resistant could effectively kill the bacteria. Different subpopulations within the same strain were resistant to different drugs, allowing the combination to target all the bacteria.

The team also tested their approach on two isolates of pan-resistant Klebsiella pneumoniae. One of these, Nevada-2016, was collected from a patient who died in 2016 and was resistant to 26 antibiotics, including colistin. Laboratory experiments showed that a combination of two antibiotics targeting Nevada-2016’s heteroresistance successfully eliminated the bacteria.

Further testing in mice infected with a deadly heteroresistant strain, AR0040, demonstrated that using the correct antibiotic combination cured the animals of infection.

While using antibiotic combinations is not a new concept, this study explains why it can work: heteroresistance allows different drugs to attack distinct subpopulations within the same bacterial culture. However, if a strain develops heteroresistance to multiple antibiotics simultaneously, this strategy may be less effective.

“We are saying: Don’t toss those drugs in the trash, they may still have some utility,” Weiss notes. “They just have to be used in combination with others. Testing bacterial strains to figure out effective drug mixes isn’t so different from testing for resistance to individual antibiotics, making this strategy pragmatically viable.”