'Conversation stoppers' fight deadly bacterial infections




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'Conversation stoppers' fight deadly bacterial infections

SAN FRANCISCO - Bacterial infections are becoming more deadly worldwide due to increased resistance to antibiotics. Now, chemists at the University of Wisconsin-Madison have developed a powerful strategy to fight these deadly infections: Instead of killing the bacteria directly, the scientists designed a group of compounds that can block the chemical signals that the bacteria use to communicate in an effort to stop their spread.

These compounds, small organic molecules that they call 'conversation stoppers,' could help deliver a powerful one-two punch to knock out deadly infections when combined with the killing power of antibiotics, the scientists say. In addition, these 'conversation stoppers' do not target bacterial growth, so the potential for the development of bacterial resistance is minimized. This research, which is funded by the National Institutes of Health, could lead to new drugs to fight infections, was described today at the 232nd national meeting of the American Chemical Society.

"There is an urgent, global need for new antibacterial therapies," says study leader Helen Blackwell, Ph.D., an assistant professor of chemistry at the University. "The ability to interfere with bacterial virulence by intercepting bacterial communication networks represents a new therapeutic approach and is clinically timely."



Bacteria use chemical signals to initiate the majority of human infections. When these signals reach a certain threshold (in a process known as quorum sensing), pathogenic bacteria will change their mode of growth and produce virulence factors that lead to infection. These chemical signals also trigger the bacteria to produce slimy biofilms that cloak the bacteria and make the colony physically resistant to antibiotics.

Attempts to block bacterial quorum sensing are being conducted by a growing number of research groups. Many of these studies have focused on a group of small molecules called N-acylated L-homoserine lactones (AHLs), which are key signaling molecules used by Gram-negative bacteria.



Bacteria can aggregate and produce dangerous biofilms that make them physically resistant to antibiotics. Researchers at the University of Wisconsin-Madison have designed a group of compounds that show promise for blocking biofilm formation, a strategy that could one day result in new drugs to fight infections.

But discovery of these molecules has been a relatively slow process until now. Blackwell and her associates have found that the use of 'microwave-assisted chemistry,' a novel laboratory technique for heating chemical reactions using microwaves, can dramatically accelerate the synthesis of AHL analogs that can either block or stimulate bacterial communication.

"Using microwave heating and combinatorial techniques to generate libraries of molecules, we can now produce and test in one day a group of compounds that previously would have taken a month to study using conventional techniques," Blackwell says.

So far, the researchers have identified at least two compounds that show particular promise at blocking biofilm formation in Pseudomonas aeruginosa, a bacterium that is a common cause of death in people with cystic fibrosis, AIDS and severe burns. In collaborative research with Fred Ausubel, Ph.D., a molecular biologist at Massachusetts General Hospital in Boston, Blackwell and her colleagues demonstrated that several of these compounds can extend the lives of worms infected with P. aeruginosa.

Recently, Blackwell designed 'conversation stoppers' that are specific to one bacterial strain and not others, allowing more efficient, selective attack on specific bacterial strains. This selectivity can help avoid disrupting beneficial bacteria, such as those in the gut that aid digestion, she says.

Some 'conversation stoppers' also hold promise for fighting crop diseases, biofilm formation on medical implants and catheters, and even bioterror agents. More studies are needed, says Blackwell, adding that her compounds haven't been tested in humans or plants but says that those tests are anticipated.

Compounds in cranberry juice show promise as alternatives to antibiotics

A group of tannins found primarily in cranberries can transform E. coli bacteria, a class of microorganisms responsible for a host of human illnesses, including urinary tract infections, in ways that render them unable to initiate an infection.

WORCESTER, Mass. – September 8, 2006 – Compounds in cranberry juice have the ability to change E. coli bacteria, a class of microorganisms responsible for a host of human illnesses (everything from kidney infections to gastroenteritis to tooth decay), in ways that render them unable to initiate an infection. The results of this new research by scientists at Worcester Polytechnic Institute (WPI) suggest that the cranberry may provide an alternative to antibiotics, particularly for combating E. coli bacteria that have become resistant to conventional treatment.

The new findings, which will be presented on Sunday, Sept. 10, at the annual meeting of the American Chemical Society in San Francisco, for the first time begin to paint a detailed picture of the biochemical mechanisms that may underlie a number of beneficial health effects of cranberry juice that have been reported in other studies over the years.

Many of those studies have focused on the ability of cranberry juice to prevent urinary tract infections (UTIs), which each year affect eight million people–mostly women, the elderly, and infants-resulting in $1.6 billion in health care costs. Until now, scientists have not understood exactly how cranberry juice prevents UTIs and other bacterial infections, though they have suspected that compounds in the juice somehow prevent bacteria from adhering to the lining of the urinary tract. The new findings reveal how the compounds interfere with adhesion at the molecular level.

The new results will be incorporated in two presentations during a session that runs from 8:30 to 11:40 a.m. in the Windsor Room of the Sir Francis Drake Hotel.

The research, by Terri Camesano, associate professor of chemical engineering at WPI, and graduate students Yatao Liu and Paola Pinzon-Arango, and funded, in part, by the National Science Foundation, shows that a group of tannins (called proanthocyanidins) found primarily in cranberries affect E. coli in three devastating ways, all of which prevent the bacteria from adhering to cells in the body, a necessary first step in all infections:

* They change the shape of the bacteria from rods to spheres.

* They alter their cell membranes.

* They make it difficult for bacteria to make contact with cells, or from latching on to them should they get close enough.

For most of these effects, the impact on bacteria was stronger the higher the concentration of either cranberry juice or the tannins, suggesting that whole cranberry products and juice that has not been highly diluted may have the greatest health effects.

The new results build on previously published work, in which Camesano and her team showed that cranberry juice causes tiny tendrils (known as fimbriae) on the surface of the type of E. coli bacteria responsible for the most serious types of UTIs to become compressed. Since the fimbriae make it possible for the bacteria to bind tightly to the lining of the urinary tract, the change in shape greatly reduces the ability of the bacteria to stay put long enough to initiate an infection.

More recently, Camesano and Liu have shown that chemical changes caused by cranberry juice also create an energy barrier that keeps the bacteria from getting close to the urinary tract lining in the first place.

New work by Camesano and Pinzon-Arango shows that cranberry juice can transform E. coli bacteria in even more radical ways. The researchers grew E. coli over extended periods in solutions containing various concentrations of either cranberry juice or tannins. Over time, the normally rod-shaped bacteria became spherical-a transformation that has never before been observed in E. coli.

Remarkably, the E. coli bacteria, all of which fall into a class called gram-negative bacteria, began behaving like gram-positive bacteria-another never-before-seen phenomenon. Since gram-negative and gram-positive bacteria differ primarily in the structure of their cell membranes, the results suggest that the tannins in cranberry juice can alter the membranes of E. coli.

A final, more preliminary result that will be presented at the ACS meeting suggests that E. coli bacteria exposed to cranberry juice appear to lose the ability to secrete indole, a molecule involved in a form of bacterial communication called quorum sensing. E. coli use quorum sensing to determine when there are enough bacteria present at a certain location to initiate a successful infection.

"We are beginning to get a picture of cranberry juice and, in particular, the tannins found in cranberries as, potentially potent antibacterial agents," Camesano says. "These results are surprising and intriguing, particularly given the increasing concern about the growing resistance of certain disease-causing bacteria to antibiotics."



A public health lesson from 9/11: To curb the flu, limit flights

Analysis shows a delayed 2001-2002 influenza season

A detailed analysis of influenza patterns indicates that the sharp dip in air travel after September 11, 2001 slowed flu spread and delayed the onset of the 2001-2002 U.S. flu season, report researchers at Children's Hospital Boston. Their findings, published in the September 12, 2006 issue of the online journal PLoS Medicine, suggest that limiting airline volume could buy critical time during a flu pandemic.

Most previous investigations of the effect of air travel on influenza spread have relied on simulations of flu activity rather than actual data.

"The post-September 11th flight ban was a natural experiment on the effect of flight restrictions on disease spread," says John Brownstein, PhD, the paper's lead author and a faculty member of the Children's Hospital Informatics Program (CHIP) at the Harvard-MIT Health Sciences and Technology program. "For the first time we've been able to show, using real data, that air travel spreads the flu, suggesting that reducing the number of air passengers might ameliorate a flu pandemic."

The spread of avian flu (H5N1) in Asia and Europe, including some likely cases of person-to-person transmission, has intensified debate over whether flight restrictions should be imposed to curb emerging flu pandemics. Both the World Health Organization (WHO) and the United States government are considering such restrictions.

Using data on influenza mortality from the Centers for Disease Control and Prevention (CDC), Brownstein and senior investigator, Kenneth Mandl, MD, MPH, a CHIP faculty member and an attending physician in Children's Department of Emergency Medicine, measured the rate of influenza spread across the U.S. during nine flu seasons, from 1996-97 to 2004-05.

During the first five flu seasons, flu mortality consistently peaked on or around February 17. But in the flu season after September 11, 2001, the peak was delayed until March 2, nearly two weeks later than average. In subsequent years, the peaks moved back toward February 17 as airline activity resumed its pre-9/11 levels.

In addition, analysis of laboratory surveillance data from the WHO and CDC showed that in the 2001-2002 flu season, it took 53 days for flu to spread across the U.S., 60 percent longer than the average time of 33 days.

By contrast, in France, where flight restrictions were not imposed, there was no delay in flu activity during the 2001-2002 flu season.





Before and after the 9/11 attacks, influenza mortality tended to peak on or around February 17 (blue line). But in the flu season after the attacks, the peak was delayed until March 2, 2002. International airline volume for September (red line) was almost a mirror image, falling to its lowest point just after the 9/11 attacks. There was also a residual effect on air travel in 2002, leading to a later flu peak in 2003 as well (February 29). Courtesy John Brownstein, PhD, Children's Hospital Informatics Program

Brownstein and Mandl, both also of Harvard Medical School, then compared their data on flu spread with monthly estimates of passengers on domestic and international flights, obtained from the U.S. Department of Transportation.

For domestic flights, airline volume in November 2001 was an especially strong predictor of flu spread. With the Thanksgiving holiday, November is typically one of the busiest travel months of the year, but in 2001, many people kept close to home or sought other forms of travel.

"Thanksgiving is when new flu strains often spread across the country," Brownstein notes.

For international flights, volume during September most strongly predicted the U.S. flu peak, suggesting that September is a key month for introduction of foreign flu strains. In September 2001, international flights fell 27 percent (from 4.9 to 3.5 million passengers), and peak flu mortality that winter was delayed by two weeks. In 2002, international travel was still down by 10 percent, and the U.S. peak was again delayed.

"When we first looked at our data we noticed that the 2001-2002 flu season was highly aberrant," Mandl recounts. "At first we thought it was a problem with the data, but then we realized we were seeing the shadow of September 11th cast upon the influenza season."



Brown seaweed contains promising fat fighter, weight reducer

SAN FRANCISCO - Chemists in Japan have found that brown seaweed, a flavor component used in many Asian soups and salads, contains a compound that appears in animal studies to promote weight loss by reducing the accumulation of fat. Called fucoxanthin, the compound achieved a 5 percent to 10 percent weight reduction in test animals and could be developed into a natural extract or drug to help fight obesity, the researchers say.

The compound targets abdominal fat, in particular, and may help reduce oversized guts, the scientists say. Their study was presented today at the 232nd national meeting of the American Chemical Society.

Fucoxanthin is a brownish pigment that gives brown seaweed its characteristic color and also conducts photosynthesis (the conversion of light to energy). It is found at high levels in several different types of brown seaweed, including a type of kelp that is used in traditional Japanese miso soup. But fucoxanthin is not found in abundance in green and red seaweed, which also are used in many Asian foods, the researchers say.

The brown seaweed used in the current study was Undaria pinnatifida, a type of kelp also known as wakame, which is widely consumed in Japan. As kelp forests are found in abundance along the California coast, the new research findings could represent a potentially lucrative market if kelp - of which there are many varieties - can be developed into effective anti-obesity drugs, according to the scientists.

"I hope that our study [points to a way to] help reduce obesity in the U.S. and elsewhere," says study leader Kazuo Miyashita, Ph.D., a chemistry professor at Hokkaido University in Hokkaido, Japan. The compound appears to fight fat through two different mechanisms, he says.

The study involved more than 200 rats and mice. In obese animals fed fucoxanthin, the compound appeared to stimulate a protein, UCP1, that causes fat oxidation and conversion of energy to heat, Miyashita says. The protein is found in white adipose tissue, the type of fat that surrounds internal organs. As the abdominal area contains abundant adipose tissue, the compound might be particularly effective at shrinking oversized guts, the researcher says. This is the first time that a natural food component has been shown to reduce fat by targeting the UCP1 protein, he says.

The pigment also appeared in animal studies to stimulate the liver to produce a compound called DHA, a type of omega-3 fatty acid, at levels comparable to fish oil supplementation. Increased levels of DHA reduce 'bad cholesterol' (low density lipoprotein), which is known to contribute to obesity and heart disease. But unlike fish oil supplements, fucoxanthin doesn't have an unpleasant smell, Miyashita says. No adverse side effects from fucoxanthin were reported in the mice and rats used in the study.

But eating lots of seaweed is not the quickest or most convenient path to weight loss, Miyashita cautions. He notes that a person would probably need to eat huge amounts of brown seaweed daily to cause noticeable weight loss. That's because fucoxanthin is tightly bound to proteins in the seaweed and is not easily absorbed in the form of whole seaweed. However, he hopes to extract the most active form of fucoxanthin from brown seaweed so that it can be developed into a pill that people can take daily or as needed.

Human studies are planned, the researcher says, but adds that it may take three to five years before such an anti-obesity pill is available to consumers. Until then, people should continue to eat a well-balanced diet and get plenty of exercise, he says. Funding for the current study was provided by the Japanese government.

Forgetful? You may be losing more than just your memory

ST. PAUL, Minn. - Older adults who complain their "mind is going" may be losing a part of their brain along with their memory, according to a study published in the September 12, 2006, issue of Neurology, the scientific journal of the American Academy of Neurology.

The study, which looked at 120 people over the age of 60, found people who complained of significant memory problems but still had normal performance on memory tests had reduced gray matter density in their brains even though they weren't diagnosed with Alzheimer's disease or mild cognitive impairment (MCI), which is a transition stage between normal aging and the more serious problems caused by Alzheimer's disease.

When compared to healthy individuals, the study found people who complained of significant memory problems had a three-percent reduction in gray matter density in an area known to be important for memory; there was a four-percent reduction among individuals diagnosed with MCI.

"Significant memory loss complaints may indicate a very early "pre-MCI" stage of dementia for some people. This is important since early detection will be critical as new disease modifying medications are developed in an effort to slow and ultimately prevent Alzheimer's disease," said study author Andrew Saykin, PsyD, Professor of Psychiatry and Radiology at Dartmouth Medical School in Lebanon, New Hampshire, and an affiliate member of the American Academy of Neurology.

While normal aging, MCI and Alzheimer's disease have been associated with the loss of gray matter in the brain, this is believed to be the first study to quantitatively examine the severity of cognitive complaints in older adults and directly assess the relationship to gray matter loss.

Saykin says the findings highlight the importance of cognitive complaints in older adults, and suggest that those who complain of significant memory problems should be evaluated and closely monitored over time. Memory complaints, a cardinal feature of MCI which confers high risk for Alzheimer's disease, are reported in 25 to 50-percent of the older adult population.

Replacing insulin is top-ranked breakthrough foreseen for health in developing world

Experts rank top 10 ways of improving health in poor countries from emerging stem cell and related technologies

Eliminating the need for costly insulin injections for diabetics, regenerating heart muscle after it fails, and improving resistance to disease by engineering immune cells top a list of 10 potential breakthroughs for health in developing countries seen emerging from the new world of regenerative medicine, according to a study published today in the prestigious journal Public Library of Science (PLoS) Medicine.

Conducted by University of Toronto researchers (from the McLaughlin Centre for Molecular Medicine, the Canadian Program on Genomics and Global Health, and the U of T Joint Centre for Bioethics), the study says regenerative medicine has the potential to help developing countries address a suite of disastrous health problems, foremost among them a diabetes epidemic.

However, the study notes that in developed countries, where most of the cutting-edge science research occurs today, health-related priorities differ greatly from those of developing countries, which therefore should develop their own expertise and capacity.

"Though largely neglected by the field of regenerative medicine to date, we suggest that developing countries could potentially benefit from advances in regenerative medicine to address the epidemic of non-communicable disease and other pressing health needs," the authors say.

Regenerative medicine combines know-how from diverse disciplines to repair, replace or regenerate cells, tissues or organs impaired by congenital defects, disease, trauma and other causes. It moves beyond traditional transplant and replacement therapies to include the use of stem cells, soluble molecules, genetic engineering, tissue engineering, and advanced cell therapy.

There is increasing research in regenerative medicine in both developed and developing countries. Already regenerative medicine has produced a skin substitute (Apligraf), a bone regenerating therapy (Osteocel) and other medical breakthroughs. An eye institute in India (L.V. Prasad) has used adult stem cell therapy to repair the corneas of over 125 blind patients; an estimated 60% of blindness in poor communities is treatable. Regenerative medicine holds the promise of more affordable treatments than corneal grafts and of offsetting shortages of donor material.

The study, the first of its kind:

* Identifies and prioritizes applications of regenerative medicine that could effectively improve health in developing countries;

* Assesses the feasibility of building developing countries' capacity in regenerative medicine, and

* Offers recommendations for developed and developing countries alike.

An international panel of experts was involved in the study to identify the 10 most promising applications of regenerative medicine for improving health in developing countries. 35 of 44 experts in the study placed atop their list: "Novel methods of insulin replacement and pancreatic islet cell regeneration for diabetes."

Many panellists noted the heavy health, social and economic burdens that result from widespread diabetes in developing countries. Controlling that disease would consequently reduce complications such as blindness, heart disease, chronic kidney disease and diabetic ulcers, they noted, adding that repeated insulin treatments are costly and therefore inaccessible to many developing country patients.

The 2nd-ranked application, regenerating failed heart muscle using the patient's own cells, is being successfully tested in several countries and will help address fast-rising rates of heart disease in developing countries. In addition to saving lives, such therapies could reduce the cost of treating heart failure by avoiding immune rejection and costly immunosuppressive regimens.

The 3rd-ranked application: using engineered immune cells and novel vaccination strategies to improve immunity from infectious disease, would assist countless developing country victims, many of them their societies' youngest members.



These technologies could improve a person's ability to fight off infection and new strains of HIV/AIDS, tuberculosis, hepatitis, malaria and other common diseases. The full Top 10 list is appended.
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