(Press-News.org) PROVIDENCE, R.I. [Brown University] — When a foreign object such as a catheter enters the body, bacteria may not only invade it but also organize into a slick coating — a biofilm — that is highly resistant to antibiotics. Like sophisticated organized crime rings, biofilms cannot be defeated by a basic approach of conventional means. Instead doctors and drug developers need sophisticated new intelligence that reveals the key players in the network and how they operate. New research led by biologists at Brown University provides exactly that dossier on some key proteins in the iconic bacterium E. coli.
In a paper published this week in the Journal of Biological Chemistry, the researchers describe a couple of prime suspect genes and the "toxin-antitoxin" protein pair they produce. By analyzing the structure and binding of the proteins in the exquisite detail of atomic-scale X-ray crystallography, the team at Brown and Texas A&M University makes the case that "MqsR" and "MqsA" proteins are important operators worth targeting in hopes of disrupting the formation of biofilms.
"Developing new antibiotics has been very difficult, and they all pretty much target the same few proteins," said corresponding author Rebecca Page, assistant professor of molecular biology, cell biology and biochemistry at Brown. "Our proteins belong to a family of proteins that have never been investigated for their ability to lead to novel sets of antibiotics. This really provides a new avenue."
The main role of the combination, or complex, of MqsA and MqsR is that they appear to control the transcription of many genes, including ones that govern the growth of "persister" cells, which provide biofilms with a mesh of antibiotic-resistant constituents. In normal populations, persisters are one in a million. In biofilms, they are one in a hundred.
"The MqsR:MqsA complex not only binds its own genetic promoter, but also binds and regulates the promoters of other genes that are important for biofilm formation," Page said. "This is the only known toxin-antitoxin system that is capable of doing this."
An odd bird
The MqsA antitoxin is as unusual as it is influential, Page's team reports. For one thing, the protein, which resembles a bird with wide flapping wings — Page likens it to a Klingon "Bird of Prey" ship from Star Trek — needs the metal zinc on each wing tip to keep it stable. When it's bound to its partner toxin and DNA, the antitoxin also keeps a very tight lid on the toxin's ability to operate on mRNA, squeezing key parts, or active sites, so close together (about 1 billionth of a meter) that the mRNA simply can't enter.
Because the toxin's activity is key to the health and welfare of persister and biofilm cells, the properties of the toxin-antitoxin binding that regulate them give rise to some potential drug development strategies, Page said. For most of the time, the toxin is bound by the antitoxin, allowing cells to grow. Under other conditions, the antitoxin is destroyed and the toxin is free to cleave, or disable, mRNA. That shuts off existing persister and biofilm cells from further growth, and instead keeps them in a dormant state well-protected from things like antibiotics. If that cleaving goes on too long, however, the cells will die.
So two approaches for drug development, Page said, might be to find compounds that can either keep the toxin-antitoxin pair associated all the time (so that the toxin is inactive and thus that no cleaving occurs), or keep them separated all the time (so that the toxin is active and cleaving always occurs). The zinc on the antitoxin may also prove to be a target.
The investigation is ongoing, but the word is now out on the street that for MqsA and MqsR, the heat is on.
INFORMATION:
In addition to Page, the paper's other authors are graduate student Breann Brown and Associate Professor Wolfgang Peti in Brown's Department of Molecular Pharmacology, Physiology, and Biotechnology, and Thomas Wood, professor of chemical engineering at Texas A&M.
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MADISON, WI November 8, 2010 -- Conversion of sorghum grass to ethanol has increased with the interest in renewable fuel sources. Researchers at Iowa State University examined 12 varieties of sorghum grass grown in single and double cropping systems. The experiment was designed to test the efficiency of double cropping sorghum grass to increase its yield for biofuel production.
The author of the report, Ben Goff, found that using sorghum from a single-cropping system was more effective for the production of ethanol. Since most of the ethanol currently produced in the ...
CORVALLIS, Ore. – There may be many similarities between the importance of large predators in marine and terrestrial environments, researchers concluded in a recent study, which examined the interactions between wolves and elk in the United States, as well as sharks and dugongs in Australia.
In each case, the major predators help control the populations of their prey, scientists said. But through what's been called the "ecology of fear" they also affect the behavior of the prey, with ripple impacts on other aspects of the ecosystem and an ecological significance that ...
AURORA, Colo. (Nov. 10, 2010) – New research released today takes a look at birth outcomes and maternal smoking, building urgency for more states and cities to join the nationwide smoke-free trend that has accelerated in recent years. According to the new data, strong smoke-free policies can improve fetal outcomes by significantly reducing the prevalence of maternal smoking.
The study, which was presented today at the American Public Health Association's 138th Annual Meeting & Exposition in Denver, compared maternal smoking prevalence in one Colorado city where a smoking ...
ANN ARBOR, Mich. —A diagnosis of idiopathic pulmonary fibrosis is not much better than a death sentence, given a survival rate averaging 4 to 6 years as the disease robs its victim of the ability to breathe.
But researchers at the University of Michigan have discovered a receptor in the immune system that may serve as a marker for a rapidly progressing form of the disease, which causes the body to produce excess fibrous tissue in the lungs.
More than just signaling which patients have the more aggressive form of IPF – a disease that claims about as many lives each year ...
COLUMBIA, Mo. – In modern culture, it is not considered socially acceptable for married people to have extramarital sexual partners. However, in some Amazonian cultures, extramarital sexual affairs were common, and people believed that when a woman became pregnant, each of her sexual partners would be considered part-biological father. Now, a new University of Missouri study published in the journal Proceedings of the National Academy of Sciences has found that up to 70 percent of Amazonian cultures may have believed in the principle of multiple paternity.
"In these cultures, ...
COLUMBUS, Ohio – The genes we possess not only determine the color of our eyes and hair and how our bodies grow, they might also influence the changes that occur in tumors when we develop cancer.
A study by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) suggests that our normal genetic background – the genetic variations that we inherit – contributes to the kinds of DNA changes that occur in tumor cells as cancer develops.
The researchers compared multiple ...
A novel project set in a rural community near Rochester, N.Y., to screen elderly people for unmet needs showed that, indeed, there is a great opportunity to match older adults with professional assistance. This new model of care for rural-dwelling adults is described this month in the Journal of the American Geriatrics Society.
The University of Rochester Medical Center, Livingston County Department of Health and Office for the Aging, and the Genesee Valley Health Partnership collaborated to create this program, called Livingston Help for Seniors.
In one instance, ...
Despite lack of evidence about bed rest's effectiveness, doctors annually prescribe it for roughly 1 million pregnant women to delay preterm births.
Judith Maloni, professor at the Frances Payne Bolton School of Nursing at Case Western Reserve University, said a comprehensive review of more than 70 evidence-based research articles challenges whether this is healthy for mothers — or their babies.
She makes her report in the article, "Antepartum Bed Rest for Pregnancy Complications: Efficacy and Safety for Preventing Preterm Birth," in the special women's health issue ...
CINCINNATI—It's no surprise that being a physician is a very stressful job and carries a lot of responsibility with it.
But two new studies from researchers at the University of Cincinnati (UC) indicate that the stressors arising from work in the clinic, where physicians are seeing patients one-on-one, can effectively be measured with hopes of improving patient care and physician job satisfaction.
Ronnie Horner, PhD, and C. Jeff Jacobson, PhD, both researchers in the department of public health sciences, say their studies, published in online editions of the journal ...
An estimated 26 million people, 13% of the United States population, are living with Chronic Kidney Disease (CKD), and this number continues to grow. If current trends continue, there will not be enough doctors to serve this expanding patient population.
To help address this crisis, the American Society of Nephrology (ASN) is convening a Summit on the Nephrology Workforce during its upcoming ASN Renal Week 2010 in Denver, Colorado, on November 17. Participants will discuss this crisis, its implications, and strategies to increase the number of kidney disease doctors in ...
