LIFE SCIENCE

Studies have found that new antibiotics can clear Clostridium difficile and stop reinfection


Recently, a mouse study led by the University of Notre Dame found that a new antibiotic is more effective than first-line antibiotics for Clostridium difficile infection and can significantly reduce the risk of reinfection. The results were published in the Proceedings of the National Academy of Sciences.

A new antibiotic is effective in treating Clostridium difficile infections in mice and helps prevent the formation of new spores (yellow in the figure). Photo by Jeshina Janardhanan and Yuanyuan Qian

Symptoms caused by Clostridium difficile include abdominal cramps, diarrhea, fever and, in extreme cases, severe dehydration and kidney failure. In the United States alone, 13,000 people die each year from such infections. As a result, the U.S. Centers for Disease Control and Prevention lists it as one of five antibiotic-resistant infections that are “an urgent threat.”

Mayland Chang, corresponding author of the study and a University of Notre Dame, noted that Clostridium difficile infection causes more than seven times as many deaths as the remaining four infectious diseases with an urgent threat.

Clostridium difficile usually infects the intestines after people take antibiotics to clear another infection. When people inhale airborne spores in hospitals, Clostridium difficile is able to live because antibiotics eliminate the gut microbiome. Clinically, vancomycin, the first-line antibiotic, works well against initial Clostridium difficile infection, but does not respond well to subsequent infections.

Alexander Khoruts of the University of Minnesota said vancomycin is not active against spores, and the recurrence of Clostridium difficile infection remains a big problem after a course of vancomycin.

This means that Clostridium difficile spores can quietly remain in the body and cause infection years later. Chang said about 25 percent of people infected with Clostridium difficile will go on to get a second infection, 40 percent will have a third infection, and 65 percent will have a fourth infection.

Chang’s team tried to break the cycle of reinfection. They searched a database of antimicrobial molecules, screened for compounds that were active against a specific binding protein in Clostridium difficile, and came up with two compounds: oxadiazole 1 and oxadiazole 2. In vitro tests, both compounds killed Clostridium difficile when used in the same concentration as vancomycin.

Oxadiazole is quickly absorbed into the bloodstream, but for intestinal infections, this is a problem and requires drugs to stay in the intestines. Oxadiazole 2 quickly entered the blood of mice, so the team did not study it further. However, oxadiazole 1 is not absorbed into the blood. In a series of Clostridium difficile infection studies, the researchers found that oxadiazole 1 protected mice from death 30 percent better than vancomycin.

Perhaps the most promising outcome is the way drugs can stop persistent infections. Oxadiazole 1 blocks two proteins that help Clostridium difficile form resistant spores. Three weeks after treatment, mice treated with vancomycin still had detectable spores in their feces and continued to recurrent infections. Mice treated with oxadiazole 1 had no quantifiable spores detected during the study and were not reinfected.

This finding may hint at a new approach to treating Clostridium difficile infection in humans. Currently, another promising treatment is fecal microbiota transplantation, in which patients receive fecal microbes from an uninfected donor to rebuild a healthy gut microbiome.

Recently, the U.S. Food and Drug Administration has approved two commercialized drugs based on fecal microbiota transplantation, but these drugs are not always effective. Khoruts believes that new drugs need to be developed to treat Clostridium difficile. (Source: China Science News Xin Yu)

Related paper information:https://doi.org/10.1073/pnas.2304110120



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