Research provides clues to antibiotic resistance

Posted on Tuesday, February 21st, 2012

An analysis of the genome of a superbug has yielded crucial, novel information that could aid efforts to counteract the bacterium’s resistance to an antibiotic of last resort. The results of the research led by scientists from the Division of Infectious Diseases are published in the Sept. 8 issue of the New England Journal of Medicine.

Superbugs are bacteria that are resistant to multiple antibiotics and represent one of the most challenging health problems of the 21st century. Infections caused by these bacteria can lead to longer illnesses, extended hospital stays, and, in some instances, death. Antibiotic resistance is on the rise, and alternative treatments are frequently suboptimal.

Researchers focused on a superbug called vancomycin-resistant enterococci (VRE), which is an intestinal bacterium that is resistant to multiple antibiotics, particularly vancomycin, a drug that has been used for treatment of potentially lethal hospital-associated infections.

“It is the second most common bacterium isolated from patients in U.S. hospitals after staphylococci,” says Cesar Arias, M.D., Ph.D., the study’s lead author and principal investigator and associate professor of internal medicine.

“The problem is that VRE has become so resistant that we don’t have reliable antibiotics to treat it anymore,” Dr. Arias says. “Daptomycin is one of the few antibiotics left with activity against VRE and is usually used as a drug of last resort. Additionally, this particular superbug is frequently seen in debilitated patients, such as those in critical care units, receiving cancer treatment, and patients receiving transplants, among others; therefore, the emergence of resistance during therapy is a big issue.”

VRE itself can develop resistance to daptomycin during treatment. To find out why, researchers compared the genomes of bacterial samples drawn from the blood of a patient with VRE bloodstream infection receiving daptomycin. The bacterium developed daptomycin resistance, and the patient subsequently died.

By comparing the genetic makeup of the bacterium before and after it developed resistance to daptomycin, the researchers were able to identify changes in genes directly tied to antibiotic resistance. “Our research provides direct substantiation that changes in two bacterial genes are sufficient for the development of daptomycin resistance in VRE during therapy,” Arias said.

“These results lay the foundation for understanding how bacteria may become resistant to daptomycin, which opens immense possibilities for targeting the functions encoded by these mutated genes,” says Barbara Murray, M.D., coauthor and director of the Division of Infectious Diseases.

“This study identified genes never before linked to antibiotic resistance in enterococci,” said Murray, holder of the J. Ralph Meadows Professorship in Internal Medicine. “The genomic approach used in the study is very powerful and was able to pinpoint exactly the specific genes and mutations within them that resulted in the failure of daptomycin (CUBICIN®) therapy and contributed to the fatal outcome of the patient.”

Arias’ laboratory is doing additional research needed to determine the precise mechanisms by which the gene changes allow the bacterium to defeat the antibiotic.

“There are mutations that appear to alter the bacterial cell envelope, which is the target of the antibiotic. The modifications brought about by the gene mutations may change the cell envelope to avoid the killing by these antibiotics. We believe these changes are a general mechanism by which bacteria protect themselves,” Dr. Arias says.

“Twenty years ago antibiotic-resistant bacteria more often caused hospital-acquired infections in people with underlying illness or advanced age,” says Herbert DuPont, M.D., holder of the Mary W. Kelsey Distinguished Professorship in the Medical Sciences and director of the Center for Infectious Diseases at the School of Public Health. “Now, resistant bacteria are often seen in the community in otherwise healthy people, making treatment very complicated.”

This research would be a step toward the development of much-needed drugs, Dr. Murray adds.

The study titled “Genetic Basis for In Vivo Daptomycin Resistance in Enterococci” received support from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

— Robert Cahill, Office of Advancement, Media Relations

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