Ancient Bacteria Offer New Line Of Attack On Cystic Fibrosis

Main Category: Cystic Fibrosis
Also Included In: Infectious Diseases / Bacteria / Viruses
Article Date: 18 Dec 2008 - 1:00 PDT

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MIT researchers have found that the pigments responsible for the blue-green stain of the mucus that clogs the lungs of cystic fibrosis (CF) patients are primarily signaling molecules that allow large clusters of the opportunistic infection agent, Pseudomonas aeruginosa, to organize themselves into structured communities.

This new insight about the leading cause of death of people with CF suggests that the phenazine-processing machinery could become a potential target for drugs to treat P. aeruginosa infections in CF patients, according to the research team, led by Dianne K. Newman, the John and Dorothy Wilson Professor of Biology and Geobiology. Newman and postdoctoral fellow Lars Dietrich will report the findings Tuesday at the American Society for Cell Biology annual meeting in San Francisco.

P. aeruginosa appears as a classic opportunistic infection, easily shrugged off by healthy people but a grave threat to those with CF, which chokes the lungs of its victims with sticky mucus. For decades, the blue-green pigments known as phenazines have been wrongly regarded as antibiotics, generated by P. aeruginosa to kill off the microbe's bacterial competitors in the lungs.

"We have a long way to go before being able to test this idea, but the hope is that if survival in the lung is influenced by phenazine - or some other electron-shuttling molecule or molecules - tampering with phenazine trafficking might be a potential way to make antibiotics more effective," said Newman, whose lab investigates how ancestral bacteria on the early Earth evolved the ability to metabolize minerals.

Newman and Dietrich looked at phenazines from an evolutionary perspective, and using RNA arrays to probe all of the small molecules' actions, they discovered that phenazines are not mere redox-active weapons but are molecules that activate the transcription factor SoxR.

In Escherichia coli and other closely related bacteria, SoxR regulates the response to superoxide stress and appears to be utilized to regulate a handful of genes that might be involved in the transport and modification of redox-active signals.

By manipulating phenazine activity in colonies of P. aeruginosa grown in the lab, the MIT scientists learned that these molecules create a smooth biofilm surface under which the colony can prosper in anaerobic bliss. The less phenazine available, the more wrinkled and less strong the colony surface becomes.

A thick biofilm also develops in the lungs of patients with CF infected with P. aeruginosa. Sealed under the biofilm are the pseudomonads that have adapted to the patients' lungs, developed antibiotic resistance and formed large anaerobic colonies.

Most people with CF die from a cascade of damaging lung infections. Pathogenic bacteria such as Staphylococcus aureus weaken the CF patient, but it is the onset of P. aeruginosa infection that signals a dangerous turn.

(adapted from a news release issued by the American Society for Cell Biology)

MIT