Cedars-Sinai investigators have detailed a new way that bacteria use iron to cooperate and resist antibiotic treatment. The study, led by the Cedars-Sinai departments of Biomedical Sciences and Pathology and Laboratory Medicine, is published in the peer-reviewed journal Nature Microbiology and is the first to show this type of antibiotic cross-protection.
More than 2.8 million antimicrobial-resistant infections occur in the U.S. each year, and more than 35,000 people die as a result, according to the Centers for Disease Control and Prevention. To prevent this, investigators contend they must develop new drugs to fight multidrug-resistant bacteria. One new therapeutic option is the antibiotic cefiderocol.
“Cefiderocol uses iron—an essential nutrient for bacteria—to sneak into the bacterial cell where it kills the disease,” said Peter Jorth, PhD, assistant professor in the departments of Biomedical Sciences, Medicine, and Pathology and Laboratory Medicine at Cedars-Sinai, and corresponding author of the study. “Our study focused on how one species of multidrug-resistant bacteria, called Pseudomonas aeruginosa, could evolve resistance to cefiderocol.”
Pseudomonas aeruginosa is a bacterium that can cause a variety of infections, including sepsis, pneumonia and urinary tract infections.
Using whole genome sequencing, Cedars-Sinai investigators discovered that Pseudomonas aeruginosa could evolve in more than 20 different ways to resist cefiderocol. The most common genetic mutation found in more than 70% of bacteria, Jorth said, caused drug-resistant Pseudomonas aeruginosa to shield drug-sensitive bacteria from antibiotic killing.
Previous studies have shown that cross-protection against other antibiotics involved enzymes that degraded the drugs.
“However, we found that cefiderocol cross-protection did not use an enzyme,” Jorth said. “Instead, cefiderocol cross-protection used bacterial small molecules that stole iron from the antibiotic and prevented it from entering the bacterial cell.”
Based on this knowledge, investigators now believe that intermittent—versus continuous— treatment with cefiderocol could limit the spread of drug resistance and improve cefiderocol effectiveness.
“These findings change what we know about bacterial cooperation,” said David Underhill, PhD, chair of the Department of Biomedical Sciences, who was not involved in the research study. “The data also suggest new ways that the cefiderocol antibiotic can be used to treat patients, although this requires additional investigation.”
As a next step, Jorth and the research team plan to test new treatment strategies using cefiderocol.
“We hope that by intermittently treating individuals with cefiderocol—versus continuously—we will limit the development of resistance,” Jorth said. “We are now using mathematical modeling to predict the best cycling strategies for cefiderocol dosing, which we plan to test in our laboratories.”
Other Cedars-Sinai authors involved in the study include Anna Clara M. Galdino, Mylene Vaillancourt, Diana Celedonio and Kara Huse. Other authors include Yohei Doi and Janet S. Lee.
This research was funded by grant numbers JORTH17F5, JORTH19P0, and MILESI21F0 from the Cystic Fibrosis Foundation and grant numbers K22AI127473, R21AI151362 and R01AI14642 from the NIH/National Institute of Allergy and Infectious Diseases and R01Hl136143 from the NIH/National Heart, Lung, and Blood Institute. (Newswise/KV)