Antibiotics are medicines that can fight infections and save millions of lives each year. However, the overuse of antibiotics may contribute to bacterial infections becoming resistant to antibacterial medications, and antibiotics may weaken the immune system by harming helpful microbes that reside in our gut. Side effects of antibiotics weakening the body’s defense system may include Clostridioides difficile infections or the development of allergic, metabolic, immunological, or inflammatory diseases.

Scientists from the Typas group at EMBL Heidelberg, the Maier lab at the Cluster of Excellence “Controlling Microbes to Fight Infections” at the University of Tübingen, and collaborators sought to determine antibiotics’ effects on gut microbes.

Their findings were published in the journal Nature in a paper titled, “Unravelling the collateral damage of antibiotics on gut bacteria.”

“Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease,” the researchers wrote. “Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species.”

“Many antibiotics inhibit the growth of various pathogenic bacteria. This broad activity spectrum is useful when treating infections, but it increases the risk that the microbes in our gut are targeted as well,” explained Lisa Maier, PhD, the DFG Emmy Noether group leader at the University of Tübingen. Maier is an alumna of the Typas lab and one of the two lead authors of the study.

“So far, our knowledge of the effects of different antibiotics on individual members of our gut microbial communities has been patchy. Our study fills major gaps in our understanding of which type of antibiotic affects which types of bacteria, and in what way,” said Nassos Typas, PhD, senior scientist and group leader at EMBL Heidelberg.

Building on a previous study from EMBL’s Typas, Bork, Patil, and Zeller groups, the scientists analyzed how 144 antibiotics affected the growth and survival of up to 27 bacterial strains commonly inhabiting our guts. The researchers determined the concentrations at which a given antibiotic would affect these bacterial strains for more than 800 antibiotic–strain combinations, expanding existing datasets on antibiotic spectra in gut bacterial species by 75%.

The researchers discovered macrolides and teracyclines “…inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal and human gut microbiomes.”

“We didn’t expect to see this effect with tetracyclines and macrolides, as these antibiotic classes were considered to have only bacteriostatic effects—which means that they stop bacterial growth, but don’t kill bacteria,” added Camille Goemans, PhD, a postdoctoral fellow in the Typas group. “Our experiments show that this assumption is not true for about half of the gut microbes we studied. Doxycycline, erythromycin, and azithromycin, three commonly used antibiotics, killed several abundant gut microbial species, whereas others they just inhibited.”

To reduce the collateral damage of tetracyclines and macrolides, the scientists screened for drugs that antagonized the antibiotic activity against Bacteroides species but not against relevant pathogens. The researchers identified several non-antibiotic drugs that could help these gut microbes and other related species.

“Our approach that combines antibiotics with a protective antidote could open new opportunities for reducing the harmful side effects of antibiotics on our gut microbiomes,” explained Maier. “No single antidote will be able to protect all the bacteria in our gut— especially since those differ so much across individuals. But this concept opens up the door for developing new personalized strategies to keep our gut microbes healthy.”