A targeted antibiotic designed for treatment of staph infections caused fewer changes to the gut microbiome of mice than did common broad-spectrum antibiotics. St. Jude Children's Research Hospital scientists led the study, which provides the first evidence that a pathogen-selective approach to antibiotic development minimizes disruption of the gut microbiome that leaves patients at a risk for a variety of metabolic and immune disorders. The experimental drug is being developed by the global pharmaceutical company Debiopharm International.
The microbiome includes trillions of bacteria and other microorganisms that cover the human body and line the intestines. Broad-spectrum antibiotics have saved countless lives, but the drugs also take a toll on beneficial bacteria in the gut microbiome. The microbiome is essential for proper nutrition and immune function. Repeated use of broad-spectrum antibiotics early in childhood has been linked to gut microbiome changes that increase patients' short-term risk for secondary infections as well as obesity and celiac disease later in life.
"In this study, we demonstrated that the pathogen-selective approach to antibiotic development is an effective way to minimize collateral damage to beneficial bacteria in the gut microbiome," said corresponding author Charles Rock, Ph.D., a member of the St. Jude Department of Infectious Diseases. "Such treatment strategies will become increasingly important for use in antibiotic drug design thanks to the growing awareness of the vital role that the gut microbiome plays in digestion and immune protection."
The research focused on the experimental drug Debio 1452, which works by blocking an enzyme essential for the growth and spread of Staphylococcus aureus (staph) but few other bacteria. Rock and his colleagues have a long-standing research interest in the enzyme, named FabI, as a promising target for developing an antibiotic against staph. The infections pose a significant risk to pediatric cancer patients with compromised immune systems.
In research that appears today online ahead of print in the scientific journal Antimicrobial Agents and Chemotherapy, the scientists compared how Debio 1452 and four broad-spectrum oral antibiotics affected gut microbiome of mice. The other antibiotics used in the study were linezolid, clindamycin, moxifloxacin and amoxicillin. The antibiotics were administered daily for 10 days. A control group of mice received an inactive agent.
DNA extracted from stool samples collected before, during and for 27 days after treatment was used to calculate the quantity of bacteria in the gut. Next-generation sequencing technology was used to identify the bacteria present. The results showed that broad-spectrum antibiotics caused a 100- to 4,000-fold decrease in the microbiome population abundance. Bacterial diversity also shrank dramatically. Bacterial quantity recovered within seven days, but bacterial diversity did not for mice that received broad-spectrum antibiotics.
In contrast, Debio 1452 did not lead to significant reductions in microbiome quantity in mice and only minor changes in bacterial diversity. Two days after treatment ended, the bacterial quantity and diversity were indistinguishable from untreated mice.
"This study suggests that by targeting staph specifically, the bacterial good guys in the gut microbiome stay to help prevent secondary infections and other problems that pose a risk to seriously ill patients," said first author Jiangwei Yao, Ph.D., a staff scientist in Rock's laboratory.
The other authors are Robert Carter and Jason Rosch, both of St. Jude; and Grégoire Vuagniaux and Maryse Barbier, both of Debiopharm International, Lausanne, Switzerland.
The research was funded in part by a grant (GM034496) from the National Institutes of Health; Debiopharm and ALSAC.