Daily Archives: January 8, 2017

Click for chemistry

Companies wanting to use new chemicals in their products and requiring a thorough knowledge of the substances’ properties prior to product launch can now breathe a sigh of relief. The same applies to researchers and authorities, for example, whose work involves approving chemical substances, as the new Danish QSAR database—the first of its kind in the world—contains finished analyses of the substances for online access. The database is located on DTU Food’s website. Here, over the past decade, a huge server has been packed with massive volumes of data and advanced software.


The result is a lightning-fast chemical database containing unprecedented volumes of information on the properties of more than 600,000 chemical substances.

Danish Environmental Protection Agency uses it on a daily basis

Magnus Løfstedt, Deputy Head of Division at the Danish Environmental Protection Agency, says that he uses the Danish QSAR database almost daily.

“A chemical name doesn’t tell you much about substance toxicity—here QSAR is a great help, as it saves us a lot of time. However, if you are planning to use the results in connection with substance regulation, for example, you will need further data backed up by expert assessment.”

It began with tadpoles

The first QSAR models were developed more than a century ago. Here, researchers tested anaesthetic on tadpoles to identify a correlation between the effect of the substances and their chemical properties.

It turned out that the more lipophilic the substances were—i.e. the better they mixed with fats—the better their anaesthetic properties. The results were recorded using logarithmic paper and pencil.

Fortunately, modern QSAR methods and powerful computers eliminate the need to use tadpoles as laboratory animals. The system is able to predict how a substance will behave in a trial environment—without prior testing in the laboratory.

The better QSAR analyses—the fewer laboratory animals needed. On the other hand, it requires top-flight mathematical models.

Just like the weather forecast

The mathematical models in the Danish QSAR database can predict whether a substance will be harmful or not and—among other things—it is the easy access to these analyses which makes the system unique.

“A model is based on existing measurements, just like a weather forecast. We are trying to find measurements which tell us precisely what we need to know about a chemical substance,” says Eva Bay Wedebye, Chief Adviser at DTU Food.

A model is based on a training set of an effect—e.g. whether substances are oestrogen-like in laboratory tests. If, for example, you have 500 known substances that have been tested in a particular protocol in the laboratory, you can create a model predicting the effect of unknown substances based on the results of these tests.

The goal is to identify the chemical properties that make some of the 500 known substances oestrogen-like—and others not. The known substances are analysed in a multitude of ways, enabling the computer to distinguish between problematic and non-problematic chemical compounds.

To enhance analytic credibility, the Danish QSAR database displays the results from three different types of software so users can see whether the various models produce the same result. The system also provides a general prediction based on the results from all three systems.

The laboratory tests—which form the starting point for QSAR—are always subject to a degree of uncertainty. The same is true of the mathematical modelling, which is why the analyses are not 100 per cent reliable.

“For certain purposes, QSAR analyses can’t stand alone, but they can be valuable as a planning tool or in supplement laboratory testing,” says Eva Bay Wedebye.

Not limited to experts

The database is free of charge, but you need some knowledge of chemistry to benefit from the analyses.

Source: DTU


Nobel Laureate develops drug to prevent food allergies

A new drug which “fine tunes” the immune system is being developed to help prevent asthma and allergies to foods such as peanuts and shellfish.

Nobel Laureate Professor Barry Marshall from The University of Western Australia is developing an oral treatment called Immbalance, which is designed to restore balance to the immune system and desensitise allergic responses.

Barry Marshall

Barry Marshall. Credit: The University of Western Australia

Professor Barry Marshall said the drug would harness the immune properties of common bacterium Helicobacter pylori, that naturally resides in the human gut and move the allergic response down into the normal range.

“Studies in the USA show children infected with Helicobacter have a 45 per cent reduction in allergies and asthma,” Professor Marshall said.

“Now in the 21st Century as Helicobacter is disappearing, humans in response have become hyper-reactive to allergies. If we put Helicobacter back in a safe way we can move allergic people back into a normal range.

“By developing an oral product which contains non-viable Helicobacter we can get the immune advantages that Stone Age man used to get by having live bacteria, with none of the disadvantages.”

Professor Marshall’s company, Ondek, based in Perth and Sydney, has been developing the drug for the past seven years and said it can be formulated as tablets, capsules, liquids or powdered product.

“Children could spread the powder on their cereal or put it in a drink and over the course of a few months could supress their allergic response,” he said.

“We think it’s going to be 100 per cent safe. It won’t remove your immune system; it will just take the edge off.”

Australia has one of the highest allergy and asthma rates in the world and over the last 10 years has seen a 10-fold increase in referrals for food allergies, and a five-fold increase in hospital referrals for food-related severe allergy or anaphylaxis.

“It appears when everything is very clean and children aren’t exposed to enough infectious or non-infectious bacteria the immune system can get ramped up,” Professor Marshall said.

“They then can become more reactive to all kinds of new proteins in their diet or susceptible to pollen in the air.”

Professor Marshall will be looking to trial the drug on humans within two years and hopes to make Immbalanceavailable within five years.

Source: The University of Western Australia

Pine product offers fresh take on fine chemical synthesis

The goop from pine trees that contains compounds known as terpenes is used in the manufacture of food, cosmetics and drugs, but it might become even more valuable as a chemical reagent made through a process developed by scientists at Rice University.

The Rice lab of synthetic chemist László Kürti reported its success at creating highly efficient aminating and hydroxylating reagents from abundant and biorenewable terpenoids that promises to make the reagents’ use environmentally friendly and cost-effective.

Scientists at Rice University and their colleagues have enabled the direct transfer of primary amino and hydroxyl groups to arylmetals in a scalable and environmentally friendly fashion, meeting a formidable synthetic challenge. The researchers reported that bench-stable nitrogen-hydrogen and nitrogen-alkyl oxaziridines derived from biorenewable and robust terpenoid scaffolds can be used as efficient multifunctional reagents without deprotonation for the direct and primary amination and hydroxylation of (hetero)arylmetals. (Credit: László Kürti/Rice University - See more at: http://news.rice.edu/2016/11/28/pine-product-offers-fresh-take-on-fine-chemical-synthesis/#sthash.BbtJ7eDW.dpuf

Scientists at Rice University and their colleagues have enabled the direct transfer of primary amino and hydroxyl groups to arylmetals in a scalable and environmentally friendly fashion, meeting a formidable synthetic challenge. The researchers reported that bench-stable nitrogen-hydrogen and nitrogen-alkyl oxaziridines derived from biorenewable and robust terpenoid scaffolds can be used as efficient multifunctional reagents without deprotonation for the direct and primary amination and hydroxylation of (hetero)arylmetals. Image credit: László Kürti/Rice University

Amination introduces amino groups into organic molecules to create amines, compounds with one or more nitrogen atoms that are essential to metabolic processes. Hydroxylation incorporates oxygen-hydrogen (hydroxyl) groups into organic compounds to create alcohols or phenols. Reagents prompt or report on chemical reactions when added to a system.

The lab’s process allows for the rapid synthesis of nitrogen- and oxygen-containing molecules by using terpenoid-derived reagents at or below room temperature and in one step. These multifunctional reagents facilitate the easy transfer of oxygen and nitrogen atoms during the synthesis of a wide range of compounds and can be recycled and reused, which cuts waste and saves money for manufacturers, Kürti said.

The work is the subject of a paper this week in Nature Chemistry.

“Terpenoids like camphor and fenchone are abundant and biorenewable natural products,” said Kürti, an associate professor of chemistry at Rice. “I’m excited about their use as robust reagent scaffolds because these are about as cheap as they get.”

The new, biorenewable reagent scaffold is a middleman that allows the transfer of either nitrogen or oxygen from one molecule to another. Most reagents are used only once and discarded. The Rice researchers sought a better way to incorporate nitrogen and oxygen atoms into sometimes-delicate molecules and in the process discovered a single scaffold that could be used for the transfer of either oxygen or nitrogen.

“A long time ago, people realized it would be nice if we could have a one-step conversion of negatively charged carbons (i.e., carbanions such as those found in arylmetals) into primary amines that now contain a new carbon-nitrogen bond,” he said. “This is difficult because the nitrogen-hydrogen bonds in traditional aminating agents are very acidic and rapidly destroy the delicate carbanions.”

The researchers discovered that aminating agents with bulky terpenoid scaffolds can effectively shield the nitrogen-hydrogen bond while still exposing the nitrogen to contact with the arylmetal, he said. “We demonstrated that camphor and fenchone-derived bulky nitrogen-hydrogen oxaziridines (triangular molecules in which oxygen, nitrogen and carbon atoms are interconnected) transfer the nitrogen atom exclusively to arylmetals, while nitrogen-alkyl oxaziridines transfer the oxygen atom exclusively.

“Given that the oxaziridines are oxidizing agents, it was remarkable to see otherwise easily oxidized functionalities like thioethers, tertiary amines and conjugated double bonds survive the heteroatom-transfer process intact,” Kürti said.

He said that all of the terpene-derived oxaziridines are stable at room temperature. “We can keep it on the bench indefinitely and nothing happens to it,” Kürti said. “The previous processes were less practical since they relied on highly reactive — thus unstable — aminating agents that required storage at low temperatures.

“Oxygen and nitrogen are exceedingly important heteroatoms,” he said. “So using the same biorenewable terpenoid scaffold and making just a very minor structural change to transfer one or the other heteroatom is huge. It’s stable, it doesn’t decompose, it doesn’t use transition metals and you don’t need expensive ligands. That’s why it’s so cool.”

Rice postdoctoral researcher Hongyin Gao is the lead author of the paper. Co-authors are Rice postdoctoral researcher Zhe Zhou and graduate student Nicole Behnke; and students Doo-Hyun Kwon, James Coombs and Steven Jones and Daniel Ess, an associate professor of chemistry and biochemistry, at Brigham Young University.

Source: Rice University

Food scientist aiding fuel ethanol with new engineered bacteria

For James Steele, moving from the small fermenters where microbes make cheese, wine and beer to the multimillion-gallon tanks where corn is converted to ethanol was a natural progression.

UW-Madison food science Professor James Steele with homemade fermenters he’s using to explore genetic engineering of lactic acid bacteria, a common contaminant of many fermentation processes, including cheese, wine, beer and biofuel production. PHOTO: SEVIE KENYON - See more at: http://news.wisc.edu/food-scientist-aiding-fuel-ethanol-with-new-engineered-bacteria/#sthash.ffKse5oU.dpuf

UW-Madison food science Professor James Steele with homemade fermenters he’s using to explore genetic engineering of lactic acid bacteria, a common contaminant of many fermentation processes, including cheese, wine, beer and biofuel production. Image credit: Sevie Kenyon

Steele, the University of Wisconsin–Madison Winder-Bascom professor of food science, specializes in food, beverage and biofuel fermentation. Understanding how bacteria and yeast convert biomass into products has been his stock-in-trade for more than 30 years.

The fermentation of beer and wine can be plagued by contamination with lactic acid bacteria, which make lactic acid rather than alcohol. The same problem affects the ethanol industry.

Steele’s new company, Lactic Solutions, is advancing a judo-like remedy: using genetic engineering to transform enemy into friend. Instead of killing lactic acid bacteria with antibiotics, he’s spliced in genes for ethanol production so these organisms produce ethanol, not lactic acid.

“We are taking the problem and trying to turn it into a solution,” Steele says. The company will sell bags of bacteria to the ethanol industry to be added to the fermenter alongside the yeast that presently makes ethanol.

About 70 percent of ethanol plants fight lactic acid bacteria with antibiotics, including erythromycin, virginiamycin and penicillin. But these and other life-saving drugs are the subject of frantic concern as bacteria evolve resistance to one antibiotic after another.

The ethanol industry’s problem arises because one-third of the incoming corn goes out the door, after fermentation. This material, called “dried distillers grains with solubles,” is one of the largest sources of animal feed in the United States says Steele. “Distillers grains can carry antibiotics or bacteria that evolved in the fermentation facility to resist antibiotics.”

The result could be dangerous drugs — or dangerous bugs — in the human food supply.

According to Steele, “Tyson Foods, McDonald’s, Panera, Perdue, etc. say they will, by the end of this year or next year, eliminate the use of meat from animals fed antibiotics, so the primary way to control lactic acid bacteria in the ethanol industry is going away.”

Like the beer industry, some ethanol plants use hops to control lactic acid bacteria, but that’s more expensive and less effective than antibiotics.

As an ecologist of the microbial realm, Steele recognizes that the engineered bacteria must reproduce and survive rising levels of ethanol in the fermenter. To give them a competitive edge, a large number of engineered bacteria will be introduced as early as possible.

The reformulated lactic acid bacteria have also received a gene that produces inhibitors of garden variety lactic acid bacteria, which uses “the same systems they have evolved to compete against each other over millions of years,” Steele says. “We want to give our organisms every advantage.”

As a fringe benefit, the new bacteria consume types of sugar that are not available to the yeast. “At the end of the day, there is more ethanol produced from the same amount of corn,” Steele says, “but we would have never found this if we had not started trying to solve the antibiotics problem.”

Steele’s patent, assigned to the Wisconsin Alumni Research Foundation, covers his concept for altering lactic acid bacteria to fight competing bacteria and to make ethanol, based on unused sugars.

Lactic Solutions was incorporated in October. “We know where every potential customer is,” says Steele, the CEO. “There are about 200 ethanol plants in the United States. Indiana, Iowa and Illinois alone have 59 plants.”

As a legacy of Wisconsin’s leadership in the cheese industry, the state has two of the world’s largest producers of lactic acid bacteria. Lactic Solutions will outsource manufacturing and distribution and focus on providing service to customers and developing new strains.

Steele credits assistance from the Discovery to Product (D2P) program, cosponsored by WARF and UW–Madison. “D2P has been a remarkable experience, in preparing us to talk to customers, helping us understand things from their point of view, developing our business plan, and preparing our ‘elevator speech.’ We would not be here without D2P.”

Other assistance has come from the Business and Entrepreneurship Clinic at the Wisconsin School of Business. Steele has recently begun the gBETA incubator program, “where we’ll polish our story and learn to put together a team to run the company.”

The ethanol industry, Steele says, “understands that antibiotics are a short-term solution, and we plan to provide them with a long-term solution that also increases conversion of sugars to ethanol. Hops are way more expensive and less effective than antibiotics. We think we can do much better for less.”

Source: University of Wisconsin-Madison

Staph uses nitric oxide enzyme to colonize noses

Staph bacteria colonize nasal passages through a newly discovered function for a primeval biochemical mechanism.

The interior of the nose is a prime dwelling place for some forms of staph. More than one-third of the population has a chronic presence of Staphylococcus aureus in their nostrils and sinuses.  From there, it can get onto the hands and other skin areas.

An artist's conception of the staph bacteria responsible for MRSA, an antibiotic-resistant germ. Image credit: CDC

An artist’s conception of the staph bacteria responsible for MRSA, an antibiotic-resistant germ. Image credit: CDC

Like many bacteria, Staphylococcus aureus makes the enzyme nitric oxide synthase. In other living things that manufacture nitric oxide, the simple molecule controls many complex biological responses.  In people for example, it mediates blood pressure, nerve signals and sexual arousal.

“Much is known about nitric oxide in human physiology,” noted Dr. Ferric Fang, professor of laboratory medicine and microbiology at the University of Washington School of Medicine.  The UW Medicine researcher added, however, that the effects of nitric oxide production in bacteria have been much less clear.

Fang, along with Traci Kinkel, UW acting instructor of laboratory medicine, and a team of scientists, have been looking at this question. Their most recent findings on the essential role of the enzyme nitric oxide synthase in successful colonization by S. aureus are reported Nov. 28 in Nature Microbiology.

Kinkel explained that S. aureus typically grows into a thick group or biofilm.  If the bacteria pack densely into a confined location, eventually most of the available oxygen will be consumed

This situation can arise when staph tries to take hold and multiply inside the nose. Mucus in the nose also limits the diffusion of oxygen.

As oxygen becomes scarce, Kinkel said, the small amount of nitric oxide produced by the bacteria further restricts aerobic respiration in an effort to reduce oxygen use. This leads to the bacteria transitioning to nitrate consumption, or microaerobic respiration, to maintain energy in the low-oxygen environment.

The researchers outlined the biochemical activities stemming from nitric oxide synthase production. These regulate the transport of electrons in the pathogen’s cell membrane, and thereby maintain energy from concentration gradients across the membrane.

“We believe that this elegant mechanism is likely to represent the original, primordial function of enzymatic nitric oxide production in nature,” Fang said.  The essential bacterial mechanism appears to be evolutionarily conserved in some types of cell receptor signaling in mammals.

Also, the researchers said, in view of the many pathogenic and environmental bacteria that produce the enzyme nitric oxide synthase, and the ubiquity of low-oxygen environments in the natural world, this mechanism is likely to be a widespread bacterial response to limited oxygen.

As a survival method, the mechanism may contribute to the virulence and staying power of the disease-inducing staphylococcus bacteria. It also appears to play a role in resistance to the antibiotic daptomycin, which targets the bacterial cell membrane.

The research results suggest novel strategies for preventing staphylococcal infection by interfering with bacterial nitric oxide synthase.

Seeking alternative staph-fighting approaches is especially important now that serious strains of the bacteria no longer respond readily to strong antibiotics.

“Staphylococcus aureus colonizes an estimated two billion persons worldwide and has become a leading cause of skin, respiratory, and blood stream infections,” the researchers wrote. Deaths from methicillin-resistant S. aureus (MRSA) now exceed those caused by Human Immunodeficiency Virus (HIV) in the United States.

Source: University of Washington