Scientists Discover New Antibiotic

A new antibiotic is more effective than first-line antibiotics used to treat Clostridium difficile infections and significantly reduces the risk of reinfection, US scientists have found. The results were published on May 8 in the Proceedings of the National Academy of Sciences.

Symptoms caused by C. difficile include abdominal cramps, diarrhea and fever, and in extreme cases can lead to 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.”

Clostridium difficile infections killed more than seven times as many people as the remaining four “urgent threat” infectious diseases combined, noted study corresponding author Mayland Chang of the University of Notre Dame.

Clostridium difficile usually infects the gut after people take antibiotics to clear out another infection. When people breathe in airborne spores in the hospital, C. difficile survives because antibiotics wipe out the gut microbiome. Clinically, the first-line antibiotic vancomycin has a good effect on the treatment of C. difficile infection, but the subsequent effect is not good.

Alexander Khoruts of the University of Minnesota says vancomycin is not active against spores, and recurrence of Clostridium difficile infections remains a major problem after a course of vancomycin.

This means that C. difficile spores can live silently in the body and cause infection years later. About 25 percent of people who get C. difficile go on to get it a second time, 40 percent of people who get it a second time get it a third time, and 65 percent of people who get it a third time get it a fourth time, Chang said.

Chang’s team tried to break the cycle of reinfection. They searched a database of antibacterial molecules to screen for compounds 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 C. difficile at the same concentration as vancomycin.

Oxadiazole is quickly absorbed into the bloodstream, but that’s a problem for intestinal infections, which require the drug to stay in the gut. Oxadiazol-2 quickly entered the mice’s bloodstream, so the team did not conduct further studies. Oxadiazole 1, however, is not absorbed into the bloodstream. In a series of studies of clostridium difficile infections, researchers found that oxadiazole 1 protected mice from death 30 percent better than vancomycin.

The most promising outcome may be the way drugs stop persistent infections. Oxadiazole 1 blocks two proteins that help C. difficile form resistant spores. Three weeks after treatment, spores were still detectable in the feces of mice treated with vancomycin and continued to cause infection. Mice treated with oxadiazol-1 had no detectable detectable spores and no reinfections during the study period.

The finding could hint at a new way to treat human Clostridium difficile infections. Currently, another promising treatment is fecal microbiome transplantation, in which a patient receives fecal microbes from an uninfected donor to recreate a healthy gut microbiome.

Recently, the US Food and Drug Administration has approved two commercially available drugs based on fecal microbiome transplants, but these drugs do not always work. Khoruts believes new drugs need to be developed to treat C. difficile.