Navigation Links
Adapting to clogged airways makes common pathogen resist powerful drugs
Date:2/9/2010

People with cystic fibrosis, an inherited disease that clogs airways with thick mucous, frequently have lung infections that defy treatment. While the life expectancy for children with cystic fibrosis has increased over the past few decades, many lives are still shortened in young adulthood by the ravages of lung infections.

These chronic infections are often caused by common, environmental microbes that mutate in ways that let them live and thrive in viscous lung secretions. The same adaptations also make the pathogens less likely to be killed off by powerful antibiotics, according to a recent study led by Dr. Lucas "Luke" Hoffman, University of Washington (UW) assistant professor of pediatrics.

Surprisingly, he added, the pathogens don't need any previous exposure to the antibiotics to resist their effects. The results were published in the latest edition of PLoS Pathogens.

The researchers looked at Pseudomonas aeruginosa, a microbe that can infect a cystic fibrosis patient early in life and then undergo various changes as it establishes a chronic lung infection. Pseudomonas aeruginosa with specific alterations tend to give patients a poor outcome. Some of those alterations diminish the chances of eradicating the infection with antibiotics.

It's believed that these adaptive alterations in Pseudomonas, all of which are caused by genetic changes, could be selected for by the environment inside a patient's airways, the researchers noted. Characteristics that facilitate microbial survival begin to emerge.

The specific airway conditions that select for these genetic changes, Hoffman said, remain unclear. "But," he added, "we have some clues from what is known about airway mucus."

From the point of view of Pseudomonas, the physical properties of cystic fibrosis mucus, Hoffman said, "make it a great place for the stuff people routinely breathe in to set up shop." Cystic fibrosis secretions contain a lot of nitrates and amino acids, which Pseudomonas can use to grow.

Inside mucus plugs oxygen levels are low. Some Pseudomonas strains can live in this oxygen-poor, nutrient-rich environment. Hoffman and his team found that a mutation that occurs commonly in Pseudomonas from cystic fibrosis patients allows the pathogen to grow better in the nutrient environment in cystic fibrosis secretions. This particular mutation inactivates a gene named lasR. Pseudomonas with this mutation apparently undergo a metabolic shift: consuming less oxygen while utilizing nitrate more efficiently. lasR mutant bacteria also can handle oxidative stress resulting from an imbalance of damaging substances called free radicals forming faster than they can be detoxified.

One source of oxidative stress encountered by Pseudomonas is the antibiotic treatment that is frequently given to people who have cystic fibrosis. Antibiotics like ciprofloxacin and tobramycin kill bacteria partly by inducing the overproduction of free radicals and causing oxidative stress. Hoffman and his team found that, because these mutant microbes are resistant to oxidative stress, they were relatively resistant to these antibiotics when grown in conditions that were like cystic fibrosis mucus.

"We learned that simply by adapting to the conditions inside the airways of cystic fibrosis patients, mutated Pseudomonas can withstand the effects of ciprofloxacin and tobramycin," Hoffman said. They did not need any previous exposure to these antibiotics to reduce their susceptibility.

Hoffman and his team suspect that Pseudomonas is not the only microbe that can do this. Some of the characteristics conferred by the mutation in Pseudomonas are also exhibited in other microbes found in chronic lung infections, such as tuberculosis or the fungal pathogen, Cryptococcus neoformans, Hoffman noted. Metabolic shifts may be a way many microbes get the upper hand over their hosts and over antibiotics.

This report, Hoffman said, may point to new ideas for treating chronic lung infections. Luckily, colonies of Pseudomonas with the lasR mutation are relatively easy to identify in hospital laboratories by their distinctive iridescent sheen. Because lasR mutant Pseudomonas has been associated with worse outcomes in cystic fibrosis patients, indentifying Pseudomonas with the lasR mutation may be of prognostic value and may indicate the need for treatment with specific antibiotics like monobactams, tetracyclines, or polymyxin, whose mode of action differs from ciprofloxacin and tobramycin. Other treatment methods may be targeted at preventing adaptive changes, such as the lasR mutation, in Pseudomonas, the researchers said.

In addition to Hoffman, scientists on this study were Anthony Richardson, Ferric Fang, and Samuel Miller from the UW Department of Microbiology; Laura Houston and Jane Burns from the UW Department of Pediatrics; Hermantha Kulasekara and Mikkel Klausen from the UW Department of Genome Sciences; Wilm Martens-Habbena and David Stahl from the UW Department of Civil and Environmental Engineering; and Daniel Hassett from Department of Molecular Genetics, Biochemistry and Microbiology at the University of Cincinnati College of Medicine in Ohio. Fang and Miller both hold appointments in the UW Department of Medicine. Fang is also with the UW Department of Laboratory Medicine and Miller is also with UW Department of Genome Sciences.

The research was funded by grants from the Cystic Fibrosis Foundation, the National Institutes of Health, and the National Science Foundation.


'/>"/>
Contact: Leila Gray
leilag@u.washington.edu
206-685-0381
University of Washington
Source:Eurekalert

Related medicine news :

1. Adapting space-industry technology to treat breast cancer
2. 2009 Catholic Health Assembly to Focus on Hope in a Time of Hardship and Adapting for the Future in a Time of Health Reform
3. Adapting Gait May Help Elderly Avoid Falls
4. Adapting to pregnancy played key role in human evolution, study shows
5. Enzyme is key to clogged arteries
6. New Computerized Scans Effective for Spotting Clogged Arteries
7. High-tech CT scans: not a bad choice to test for clogged arteries
8. New White Paper Details Best Practices of an Occupational Hearing Conservation Program: US Airways
9. Data Published in Leading Respiratory Journal Reinforce Importance of Small Airways In Asthma Management
10. US Airways to Match Miles with Mercy Medical Airlift
11. Measles Spread Doesnt Depend on Airways
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/27/2016)... ... June 27, 2016 , ... ... today announced its strategic partnership with Connance, a healthcare industry leader providing ... companies’ proven, proprietary technology combine to provide health systems, hospitals and ambulatory ...
(Date:6/26/2016)... , ... June 26, 2016 , ... On June 10-11, ... of the 2016 Cereal Festival and World’s Longest Breakfast Table in Battle Creek, MI, ... the city’s history as home to some of the world’s leading providers of cereal ...
(Date:6/26/2016)... Clarkston, Michigan (PRWEB) , ... June 26, 2016 ... ... respect to fertility once they have been diagnosed with endometriosis. These women need ... but they also require a comprehensive approach that can help for preservation of ...
(Date:6/25/2016)... Aliso Viejo, California (PRWEB) , ... June 25, 2016 , ... ... preset to fit their specific project," said Christina Austin - CEO of Pixel Film ... all fully customizable and all within Final Cut Pro X . Simply select ...
(Date:6/25/2016)... ... June 25, 2016 , ... On Friday, June 10, ... Bronze Wellness at Work award to iHire in recognition of their exemplary accomplishments in ... the 7th annual Maryland Workplace Health & Wellness Symposium at the BWI Marriott in ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... 2016  Collagen Matrix, Inc., ("Collagen Matrix") the ... of collagen and mineral based medical devices for ... Bill Messer has joined the company as ... the growing portfolio of oral surgery, neurosurgery, orthopaedic ... joins the Collagen Matrix executive team as an ...
(Date:6/24/2016)... Mass. , June 24, 2016   ... Spaulding Rehabilitation Network,s Dean Center for Tick ... Physical Medicine and Rehabilitation, MIT Hacking Medicine, University ... for Innovation, today announced the five finalists of ... for Lyme disease.  More than 100 scientists, clinicians, ...
(Date:6/24/2016)... , June 24, 2016 ... of the "Structural Electronics 2015-2025: Applications, Technologies, ... In-Mold Electronics, Smart Skin, ... Photovoltaics Structural electronics involves electronic ... load-bearing, protective structures, replacing dumb structures such as ...
Breaking Medicine Technology: