Medical Device Daily
Not just curmudgeons will admit that people can exit the hospital with bigger problems than they came in with. One example is hospital-acquired infections, which can form so-called biofilms, often on medical devices such as catheters. New research shows how bacteria can break out of such biofilms to seed new films or become a source of recurrent infections.
When bacteria band together in biofilms, they become much more difficult to treat. For one thing, sticking together forms something of a mechanical barrier: not all antibiotics can penetrate the biofilm.
In addition, bacteria in a biofilm are in a dormant state: “They are not actively proliferating . . . so it is difficult to attack them with anything that targets dividing cells,“ Michael Otto told Medical Device Daily.
And the real problem, he added, can come not when the biofilm develops, but when it matures. “It can be a source for infections that are not necessarily biofilm infections anymore,“ he said. The process is in some ways similar to a metastasizing cancer – and like metastasis, it spells bad news for the patient. “Once they disseminate, they can do much more harm.“
Otto, who is a senior investigator at the National Institute of Allergy and Infectious Diseases, and his colleagues have identified a mechanism by which bacteria get out of the biofilm: by secreting a surfactant peptide that goes by the name phenol-soluble modulin beta, or PSM-beta.
Phenol soluble modulins in general, Otto said, were “identified first because they have proinflammatory features.“ In previous studies, Otto and his colleagues had shown that another PSM peptide, PSM-alpha, is important for turning community-acquired Methicillin-resistant Staphylococcus aureus strains virulent.
PSM-beta, he said, “has a little bit different approach to virulence. It causes chronic infections and so it doesn't really 'want to' do much damage to the host, so to speak.“
In their current work, which was published in the Dec. 6, 2010 issue of the Journal of Clinical Investigation, Otto and his colleagues showed that in animal studies, PSM-beta helps bacteria break off of established biofilms to enter the bloodstream and become a source of recurrent infections, a process known as maturation. Treating the animals with antibodies to PSM-beta could inhibit the spread of bacteria.
The authors began by identifying conditions that encouraged biofilm vs. so-called planktonic growth, and found that PSM-beta was produced when bacteria were in a biofilm.
Biofilm is a bit of a misnomer. Actually, bacteria growing in a biofilm are part of a more or less mushroom-shaped structure. Under the control of so-called quorum sensing gene expression programs, bacteria can begin to produce PSM that essentially forms channels in the mushroom, eventually disrupting the film enough to allow bacteria to escape.
Biofilm research is heavily conducted in vitro, Otto said, which can have its pitfalls. So in his opinion, an important aspect of the study is that “we took [our work] to the in vivo level.“
The authors implanted mice with catheters and tested whether cells were more likely to spread from biofilms if they came from regular bacteria, or from those engineered to lack PSM-beta. They found that engineered bacteria were far less able to spread out from biofilms on the catheters, suggesting that PSM-beta plays an important role in enabling bacteria to spread. Antibodies to the peptide also blocked the spread of infection.
In some ways, PSM-beta seems to be similar to other biofilm maturation proteins. “The forces that hold the biofilm together . . . are electrostatic interactions“ rather than covalent bonds, Otto said. Most maturators act as detergents to disrupt those interactions, allowing bacteria to escape. They also share being under the control of quorum-sensing molecules.
But in other ways, they are very different. Genetically, there does not appear to be a whole lot of similarities between biofilm maturation molecules from different bacterial species; and chemically, too, they appear to be very different from each other.
This diversity means that although biofilms are clearly a clinical problem, the results described in the JCI article do not suggest therapeutic approaches. If anything, their diversity makes biofilm maturators pretty clearly unsuited as targets.
“In principle this might be a target,“ Otto said. “But you are never going to get a broad-spectrum small molecule“ that is active against all, or even most, biofilm maturation proteins