Biofilm antibiotic resistance may be susceptible to genetic approach

November 19, 2003

HANOVER, NH--Biofilms, slimy clusters of bacteria that are resistant to antibiotics, may have a genetic chink in their armor that could be exploited to combat the infections they cause. A study led by Dartmouth Medical School (DMS) researchers used a genetic-based approach to begin to understand how biofilms can withstand antibacterial treatments.

The results of the study, published in the November 20 issue of Nature, provide an innovative model for the investigation of biofilms that may lead to the development of new methods to hamper their resilience. "We are beginning to get at some of the mechanisms that might be important to understanding the antibiotic resistance of biofilms, which is the first step in the long journey to developing a treatment, " said lead author Dr. George O'Toole, assistant professor of microbiology and immunology at DMS.

Biofilms are complex communities of bacterial cells that can survive various environmental stresses including the presence of antibiotics. These populations can form on industrial equipment, medical implants, teeth (plaque) and internal organs, and are estimated to be involved in 65 percent of human bacterial infections, according to the Centers for Disease Control and Prevention. Biofilms are of interest to those who study periodontal disease, pneumonias associated with cystic fibrosis, and the "earache" infections of the middle ear.

Conventional antibiotic therapy, usually effective against free-floating bacteria, is frequently ineffective once pathogens have formed biofilms: these surface-attached communities are up to 1,000-times more resistant to antibiotics.

The Dartmouth-led study questions prior assumptions that the structure itself confers resilience--and points to the possibility that one day, clinicians may be able to program the bacteria to be less resistant to antibiotics. "This is the first time anyone has used an unbiased genetic approach to understand why biofilms are resistant to antibiotics," said principal author Thien-Fah Mah, a postdoctoral fellow at DMS.

"One of the most vexing problems in biofilms is that when microbes band together in a biofilm they are remarkably protected from killing by antibiotics, biocides and disinfectants," said study co-author Phil Stewart, deputy director of the Center for Biofilm Engineering at Montana State University-Bozeman. "And of course we'd like an explanation for that."

Using a common pathogen, Pseudomonas aeruginosa, the researchers developed a genetic screen to look for mutant strains that were more sensitive to antibiotics. "The idea was to let the bacteria tell us which genes were important," said Dr. Mah. "Using this approach, we were able to identify a mutant of P. aeruginosa that, while still capable of forming biofilms, did not develop the high-level biofilm-resistance to three classes of antibiotics."

One antibiotic with increased success against the mutant biofilms described in this study is tobramycin, commonly used to treat patients with cystic fibrosis (CF), a disease where biofilms are thought to develop in patients' lungs. "This is a proof of concept that there may be a possibility of identifying small molecules to attack biofilm resistance, thereby rendering these microbial communities more susceptible to treatment with conventional antibiotic therapy," said Dr. O'Toole.
The research was funded in part by the National Science Foundation (NSF), NIH, the Canadian Cystic Fibrosis Foundation, Microbia, Inc. and the Pew Charitable Trusts.

The Geisel School of Medicine at Dartmouth

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