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Scientists uncover vulnerable enzyme that can be targeted to kill dangerous pathogens

August 28, 2009 By admin Leave a Comment

Washington, August 28 (ANI): A collaborative study conducted by researchers from three institutions in the U.S. has shown that an enzyme, which is essential to many bacteria, can be targeted to kill dangerous pathogens.

Experts at Burnham Institute for Medical Research (Burnham), University of Texas Southwestern Medical Center and University of Maryland have also identified chemical compounds that can inhibit this enzyme, and suppress the growth of pathogenic bacteria.

Writing about their study in the journal Chemistry and Biology, the researchers say that their findings are essential to develop new broad-spectrum antibacterial agents to overcome multi-drug resistance.

Dr. Andrei Osterman, an associate professor in Burnham’s ioinformatics and Systems Biology program, targeted the acterial nicotinate mononucleotide adenylyltransferase (NadD), an essential enzyme for nicotinamide adenine dinculeotide (NAD) biosynthesis, which has many crucial functions in nearly all important pathogens.

The bacterial NadD differs significantly from the human enzyme.

“It’s clear that because of bacterial resistance, we need new, wide-spectrum antibiotics. This enzyme is indispensable in many pathogens, so finding ways to inhibit it could give us new options against infection,” said Dr. Osterman.

The research team used a structure-based approach to search for low-molecular-weight compounds that would selectively inhibit bacterial NadD, but not the human equivalent, by screening, in silico, more than a million compounds.

In their experiments, they tested the best predicted compounds against Escherichia coli and Bacillus anthracis (anthrax), which led them to a handful of versatile inhibitory chemotypes, which they explored in detail.

Using protein crystallography, a 3D structure of the enzyme in complex with one of the inhibitors was solved providing guidelines for further drug improvement.

“This is proof-of-concept that NadD is a good target to create antibacterial agents. This knowledge will be useful for both biodefense and public health. The next step is to find better inhibitors. We do not have a silver bullet yet, but we are certainly hitting a golden target,” said Dr Osterman.

The research was supported by a grant from the National Institute of Allergy and Infectious Diseases. (ANI)

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Hearing impaired can access prime time news on Doordarshan

April 5, 2009 By admin Leave a Comment

New Delhi, April 3 (IANS) Going beyond just a weekly sign language news bulletin for the hearing impaired, national broadcaster Doordarshan will now make prime time news accessible to this section of the population through running scrolls and subtitles.

Javed Abidi, director of the National Centre for Promotion of Employment for Disabled People (NCPEDP), Friday said even though the decision had come late, India had finally joined other countries in giving the right to information to the hearing impaired population.

‘In most developed countries, subtitling of television programmes is a very normal thing. Even the not so developed nations like Thailand are doing it for their deaf citizens. Unfortunately, in India the awareness has been so low that our policymakers and decision-makers did not even think of it,’ Abidi said.

The move comes after a meeting of NCPEDP members with officials at the Prime Minister’s Office (PMO) in late March. The two sides had been discussing the issue for a while.

‘The demand for subtitling television programmes was first raised by the National Association of the Deaf (NAD) about two years ago, but the government did not take it very seriously. But after we took it up as one of our demands on World Disability Day Dec 3 last year, things started moving,’ he added.

Coming close on the heels of making government websites accessible to the blind, this decision, Abidi said, was a matter of great happiness to the disabled population and those working for their rights.

‘However, our aim is to ensure that the entire programming on television, at least as far as public broadcasters are concerned, is made accessible. We also aim to extend this dialogue with the private sector,’ he said.

‘The cost of making these changes is negligible. What is needed is awareness and sensitivity and a certain sociopolitical will on the part of the decision-makers,’ Abidi added.

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TB enzyme’s discovery brings new drug therapies closer to reality

March 28, 2009 By admin 1 Comment

London, March 28 (ANI): University of Maryland scientists have reached a step closer to developing new drug therapies to combat active and asymptomatic (latent) tuberculosis infections by characterizing the unique structure and mechanism of an enzyme in M. tuberculosis, the bacterium that causes the disease.

“The NAD+ synthetase enzyme that our study describes is absolutely essential for the survival of the tuberculosis bacteria and an important drug target. We can now use the information we have about its structure and mechanism to develop inhibitors for this enzyme,” Nature magazine quoted Barbara Gerratana, an Assistant Professor of Chemistry and Biochemistry, whose research team included graduate student Melissa Resto and Assistant Professor Nicole LaRonde-LeBlanc, as saying.

The researchers point out that NAD+ synthetase is responsible for making NAD+, a coenzyme found in all living cells that is involved in regulating many cellular processes and in reduction-oxidation metabolic reactions.

They say that more than one biosynthetic pathway is usually involved in NAD+ production.

In humans, according to the team, NAD+ can be obtained through several different complex pathways, and not all of the pathways utilize NAD+ synthetase to produce NAD+.

However, there are only two pathways involved in producing NAD+ in the tuberculosis bacterium, and both depend on the activity of NAD+ synthetase to obtain NAD+.

“We are optimistic about the potential for developing new drugs that will effectively target this enzyme in TB and minimize side effects to humans, since we have NAD+ biosynthetic pathways that are independent of the NAD+ synthetase activity,” Gerratana said.

Current treatment of tuberculosis targets the active tuberculosis bacterium, and has little effect on the non-replicating bacterium.

“If we don’t tackle latent tuberculosis, this disease will not be eradicated,” Gerratana said.

A research article on the researchers’ observations has been published in the journal Nature Structural and Molecular Biology. (ANI)

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How the body clock controls metabolism and ageing

March 20, 2009 By admin Leave a Comment

Washington, Mar 20 (ANI): In a study on mice, a team of scientists have found how the biological circadian clock mechanism in animals corresponds with processes that control aging and metabolism.

The findings by researchers at Washington University School of Medicine in St. Louis and Northwestern University can explain why the weakening of the circadian rhythm with age could contribute to age-related disorders, such as insulin resistance and type 2 diabetes.

“Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm. This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It could also yield new interventions to alleviate metabolic disorders such as obesity and diabetes,” said one of the lead authors, Dr. Shin-ichiro Imai.

In an earlier study, Imai demonstrated that a gene called SIRT1 was at the centre of a network that regulates aging.

SIRT1 coordinates metabolic reactions throughout the body and manages the body’s response to nutrition. The gene is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals.

“Under nutritional scarcity, SIRT1 may delay aging and extend life span to assure survival until food becomes more readily available,” explained Imai.

The researcher had earlier shown that interfering with the circadian clock of mice led to metabolic complications, including obesity and type 2 diabetes.

The new research has linked the circadian clock to SIRT1 through a key metabolite that serves as the energy currency of the body.

Thus, the researchers have defined a biochemical mechanism by which the body’s metabolic and nutritional status can directly drive the oscillation of the body’s daily clock as well as influence aging and longevity.

The new finding points potentially to innovative ways to correct metabolic disorders and improve health as people age.

In the study on laboratory mice, the researchers found a daily oscillation of the metabolite NAD (nicotinamide adenine dinucleotide), an important compound that is the body’s way of exchanging energy and moving it where it’s needed.

“Seeing this striking abnormality in the NAD levels was like discovering the cause of a disease in a patient after running a blood test,” said one of the co-authors of the study.

The researchers found that the NAD rhythm was linked to the daily rise and fall of the activity of “clock” genes, the genes that serve as the gears that run the body’s internal clock.

Also, they discovered that the clock genes directly interact with a biochemical process that produces NAD.

NAD is required for SIRT1 to function, suggesting that SIRT1 activity increased and decreased along with NAD oscillation in the mice.

Studying the mice under controlled conditions of light and dark, the researchers established the details of the NAD-SIRT1-clock gene loop and showed that it functions in liver and fat cells.

“We showed that this feedback cycle is driven by NAD. Because NAD levels reflect nutrition and energy levels, NAD’s link to the circadian and aging mechanisms makes them sensitive to the nutritional status of the organism,” said Imai.

The study has been published in the online edition of the journal Science. (ANI)

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Body clock, metabolism link could lead to cancer treatment

March 13, 2009 By admin Leave a Comment

Washington, Mar 13 (ANI): Researchers at University of California, Irvine, have found that circadian rhythms, our own body clock, regulate energy levels in cells.

According to researchers, the findings could provide greater insights into the bond between the body’s day-night patterns and metabolism. They said that the discovery could help create new ways to treat cancer, diabetes, obesity and a host of related diseases.

Also, Paolo Sassone-Corsi, Distinguished Professor and Chair of Pharmacology, and his colleagues found that the proteins involved with circadian rhythms and metabolism are intrinsically linked and dependent upon each other.

“Our circadian rhythms and metabolism are closely partnered to ensure that cells function properly and remain healthy. This discovery opens a new window for us to understand how these two fundamental processes work together, and it can have a great impact on new treatments for diseases caused by cell energy deficiencies,” Sassone-Corsi said.

Sassone-Corsi had already identified that the enzyme protein CLOCK is an essential molecular gear of the circadian machinery and interacts with a protein, SIRT1, which senses cell energy levels and modulates aging and metabolism.

In the new study, Sassone-Corsi and his colleagues show that CLOCK works in balance with SIRT1 to direct activity in a cell pathway by which metabolic proteins send signals called the NAD+ salvage pathway.

In turn, a key protein in that pathway, NAMPT, helps control CLOCK levels, creating a tightly regulated codependency between our circadian clock and metabolism.

“When the balance between these two vital processes is upset, normal cellular function can be disrupted. And this can lead to illness and disease,” Sassone-Corsi said.

He said that the findings suggest that proper sleep and diet may help maintain or rebuild this balance, and also help explain why lack of rest or disruption of normal sleep patterns can increase hunger, leading to obesity-related illnesses and accelerated aging.

The specific interaction between CLOCK and SIRT1 and the NAD+ salvage pathway also presents a starting point for drug development aimed at curbing cell dysfunction and death, thereby helping to solve major medical problems such as cancer and diabetes.

Their study appears online in Science Express. (ANI)

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Two Americans killed in southern Afghanistan

February 8, 2009 By admin Leave a Comment

Kabul, Feb.8 (ANI): Two Americans were among four persons killed on Sunday by a bomb blast in Afghanistan’s southern Helmand province.

Police officials were quoted as saying that the Taliban was behind the attack.

The other two died were an Afghan interpreter and a policeman.

Police officials said that the group was checking an improvised explosive device on Sunday in the Nad Ali district that they believed had been defused.

The International Security Assistance Force confirmed there had been a remote-controlled explosion in the district but said first reports were only that an Afghan was killed and another wounded.

The US embassy also said it could not confirm the casualties. (ANI)

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