Streptomyces in Nature and Medicine

Streptomyces in Nature and Medicine is an Account of 50 Years of Genetic Studies of the Soil Inhabiting Microbes That Produce Most of the Antibiotics Used to Treat Infections
DUBLIN, Ireland--(BUSINESS WIRE)--Research and Markets (http://www.researchandmarkets.com/reports/c81742) has announced the addition of “Streptomyces in Nature and Medicine: The Antibiotic Makers” to their offering.

This is an insiders account of 50 years of genetic studies of the soil-inhabiting microbes that produce most of the antibiotics used to treat infections, as well as anti-cancer, anti-parasitic and immunosuppressant drugs. The book begins by describing how these microbes the actinomycetes were discovered in the latter part of the nineteenth century, but remained a Cinderella group until, in the 1940s, they shot to prominence with the discovery of streptomycin, the first effective treatment for tuberculosis and only the second antibiotic, after penicillin, to become a medical marvel.

There followed a massive effort over several decades to find further treatments for infectious diseases and cancer, tempered by the rise of antibiotic resistance consequent on antibiotic misuse and over-use. The book goes on to describe the discovery of gene exchange in the actinomycetes in the context of the rise of microbial genetics in the mid-20th century, leading to determination of the complete DNA sequence of a model member of the group at the turn of the millennium. There follow chapters in which the intricate molecular machinery that adapts the organisms metabolism and development to life in the soil, including antibiotic production, is illuminated by the DNA blueprint.

Then came an up-to-the minute account of the use of genetic engineering to make novel, hybrid, antibiotics, and a topical description of techniques to learn the roles of the thousands of genes in a genome sequence, throwing a powerful light on the biology of the organisms and their harnessing for increasing antibiotic productivity. In the final chapter we return to the mycobacteria that cause tuberculosis and leprosy, the first actinomycetes to be discovered, and how methodology, in part derived from the study of the streptomycetes, is being applied to understand and control these still deadly pathogens.

About the Author

David A. Hopwood, Professor of Genetics, University of East Anglia (Emeritus)

Contents:
Preface.
Introduction.
1. Actinomycetes and Antibiotics
2. Antiobiotic Discovery and Resistance
3. Microbial Sex
4. Towards Gene Cloning
5. From Chromosome Map to DNA Sequence
6. Bacteria That Develop
7. The Switch to Antibiotic Production
8. Unnatural Natural Products
9. Functional Genomics
10. Genomics Against TB and Leprosy
Conclusion.
Notes and references.
Glossary.
Index.
For more information visit http://www.researchandmarkets.com/reports/c81742

Source: Oxford University Press


DUBLIN, Ireland--(BUSINESS WIRE)--Research and Markets (http://www.researchandmarkets.com/reports/c81742) has announced the addition of “Streptomyces in Nature and Medicine: The Antibiotic Makers” to their offering.

This is an insiders account of 50 years of genetic studies of the soil-inhabiting microbes that produce most of the antibiotics used to treat infections, as well as anti-cancer, anti-parasitic and immunosuppressant drugs. The book begins by describing how these microbes the actinomycetes were discovered in the latter part of the nineteenth century, but remained a Cinderella group until, in the 1940s, they shot to prominence with the discovery of streptomycin, the first effective treatment for tuberculosis and only the second antibiotic, after penicillin, to become a medical marvel.

There followed a massive effort over several decades to find further treatments for infectious diseases and cancer, tempered by the rise of antibiotic resistance consequent on antibiotic misuse and over-use. The book goes on to describe the discovery of gene exchange in the actinomycetes in the context of the rise of microbial genetics in the mid-20th century, leading to determination of the complete DNA sequence of a model member of the group at the turn of the millennium. There follow chapters in which the intricate molecular machinery that adapts the organisms metabolism and development to life in the soil, including antibiotic production, is illuminated by the DNA blueprint.

Then came an up-to-the minute account of the use of genetic engineering to make novel, hybrid, antibiotics, and a topical description of techniques to learn the roles of the thousands of genes in a genome sequence, throwing a powerful light on the biology of the organisms and their harnessing for increasing antibiotic productivity. In the final chapter we return to the mycobacteria that cause tuberculosis and leprosy, the first actinomycetes to be discovered, and how methodology, in part derived from the study of the streptomycetes, is being applied to understand and control these still deadly pathogens.

About the Author

David A. Hopwood, Professor of Genetics, University of East Anglia (Emeritus)

Contents:
Preface.
Introduction.
1. Actinomycetes and Antibiotics
2. Antiobiotic Discovery and Resistance
3. Microbial Sex
4. Towards Gene Cloning
5. From Chromosome Map to DNA Sequence
6. Bacteria That Develop
7. The Switch to Antibiotic Production
8. Unnatural Natural Products
9. Functional Genomics
10. Genomics Against TB and Leprosy
Conclusion.
Notes and references.
Glossary.
Index.
For more information visit http://www.researchandmarkets.com/reports/c81742

Source: Oxford University Press

Manure Management Reduces Levels Of Antibiotics And Antibiotic Resistance Genes

ScienceDaily (Dec. 3, 2007) — Antibiotic resistance is a growing human health concern. Researchers around the globe have found antibiotics and other pharmaceuticals to be present in surface waters and sediments, municipal wastewater, animal manure lagoons, and underlying groundwater. Researchers at Colorado State University (CSU) describe a study to find out if animal waste contributes to the spread of antibiotics and antibiotic resistance genes (ARG), and if they can be reduced by appropriate manure management practices.


In the study researchers investigated the effects of manure management on the levels of antibiotics and ARG in manures. The study was conducted at two scales. In the pilot-scale experiment, horse manure was spiked with the antibiotics chlortetracycline, tylosin, and monensin and compared to horse manure that was not spiked with antibiotics to determine the response of ARG in unacclimated manures. In the large-scale experiment, dairy manure and beef feedlot manure, which were already acclimated to antibiotics, were monitored over time.

The manures were subjected to high-intensity management (HIM-amending with leaves and alfalfa, watering, and turning) and low-intensity management (LIM-no amending, watering, and turning) for six months. During this time, the levels of antibiotics were monitored using high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). In addition, two types of ARG that confer resistance to tetracycline, tet(W) and tet(O), were monitored using quantitative polymerase chain reaction (Q-PCR).

In the pilot study, chlortetracycline, tylosin, and monensin all dissipated more rapidly in the HIM-manure than in the LIM-manure. In the large-scale study, feedlot manure initially had higher concentrations of the several tetracycline antibiotics than the dairy manure. After four months of treatment, tet(W) and tet(O) decreased significantly in dairy manure, but two more months of treatment were necessary for similar reductions of ARG in the feedlot manures.

The results showed that HIM was more effective than LIM at increasing the rate of antibiotic dissipation, but it was not a significant factor in reducing the levels of ARG. The length of treatment time was the main factor in reducing the levels of both antibiotics and ARG. For manures with initially high levels of antibiotics, treatment times of at least six months may be necessary for a significant reduction in levels of antibiotics and ARG. The results also provided evidence that ARG may be present for extended time periods even after antibiotics have fully dissipated.

Scientists at Colorado State University are continuing research in this area by examining full-scale local on-farm waste management practices. Together this research will lead to a better understanding of possible ARG mitigation strategies so that best management practices can be developed to reduce the effects that animal waste may have on the spread of ARG.

This research was published in the November-December issue of Journal of Environmental Quality. Funding was provided by the USDA Agricultural Experiment Station at CSU and the National Science Foundation (NSF).

Adapted from materials provided by American Society of Agronomy.

Montgomery Village Student Diagnosed With MRSA

MONTGOMERY VILLAGE, Md. -- A student at Montgomery Village Middle School has been diagnosed with MRSA, an antibiotic-resistant strain of staph infection.

The student is the first at the school to be diagnosed with methicillin-resistant Staphylococcus aureus, school officials said.It's the 43rd case in the Montgomery County school system this year.

School officials said the student is being treated and is attending class, News4's Jane Watrel reported.

Principal Edgar E. Malker and school nurse Maureen Reges released a statement urging families of students at the school to practice good hygiene and check skin regularly for lesions.

Merry King, a middle school special education teacher in Potomac, died earlier this week from MRSA.

The Montgomery school system has had 43 cases in 31 schools this school year, primarily among student athletes, said Kate Harrison, a spokeswoman for the Montgomery County school system.

Health officials said MRSA is not found only in schools, but also in places like rec centers and health clubs.

Dozens of cases of the infection have been reported in the Washington region, but exact figures are not available because doctors are not required to report MRSA to state health authorities.

Health officials said basic hygiene can prevent the spread of the disease. Washing hands and clothes and not sharing personal articles are the best safeguards, they said.

An estimated 90,000 people in the United States fall ill each year from MRSA. It is not clear how many die from the infection; one estimate put it at more than 18,000, which would be slightly higher than U.S. deaths from AIDS.

Anacor's boron-based drug stops the rot

25/06/2007 - An unusual drug that contains a crucial boron atom can effectively treat fungal infections, and could also prove invaluable in the effort to counter antibacterial drug resistance.

Scientists from the young US pharma firm Anacor developed AN2690, the first in a new class of antibiotics that contain a crucial boron atom. Together with a team from the European Molecular Biology Laboratory (EMBL) outstation in Grenoble, France, the researchers have now discovered exactly how the drug works.

"We have discovered a new compound that has the potential to treat common chronic nail infections caused by fungi [onychomycosis]," said Dickon Alley, a researcher at Anacor Pharmaceuticals.

"Now that we know how AN2690 works, the same approach could be adapted to target other aminoacyl-tRNA synthetases with editing sites and also other pathogenic microbes," said Stephen Cusack, Head of EMBL.

"We are now working towards finding related antibacterial compounds that could help counter the problem of antibiotic resistance."

Alley explained that the compound kills fungi by blocking their ability to make proteins. It does this by blocking an enzyme called leucyl-tRNA synthetase, which is involved in translation, one of the last steps in the process of turning a gene's DNA code into a protein.

The process begins when the cell makes an RNA version of the gene's code, called messenger RNA (mRNA). Ribosomes, the cell's protein synthesis machinery, then translate the mRNA into protein by stitching together the amino acids in the order specified by the message. This requires the help of molecules called transfer RNAs (tRNAs), which link the mRNA to the correct amino acid.

Leucyl-tRNA synthetase is one of a group of enzymes called aminoacyl-tRNA synthetases that attach the correct amino acid to each tRNA. Some of these enzymes have two main functional parts, or active sites: a site that links the amino acid to the tRNA, and a separate editing site that proofreads this process and removes wrongly added amino acids.

To find out how exactly AN2690 blocks leucyl-tRNA synthetase Stephen Cusack, Head of EMBL Grenoble, and his team generated crystals of the enzyme bound to tRNA in the presence of AN2690.

They then used X-rays to examine the structure of the complex. Cusack and his colleagues found that AN2690 sticks in the editing site of the enzyme where it makes a very strong bond to the end of the tRNA, trapping it on the enzyme.

This stops the enzyme working and thus blocks protein synthesis, killing the fungal cell. The mechanism crucially depends on a boron atom that is part of AN2690, which is needed to link the compound to the tRNA.

According to Anacor, it is the first time that scientists have described such a mechanism, suggesting boron containing compounds as a promising new class of drug candidates. The drug itself is currently in Phase II trials.

The pharma industry in general is watching this approach keenly. In February, Schering-Plough paid over $575m ($40m upfront) to gain the exclusive global rights to AN2690 from Anacor. Historically, several other pharma companies have also shown an interest in aminoacyl-tRNA synthetase inhibitors.

Curiously, as far back as 1999, AstraZeneca (then plain Zeneca), had a patent issued for an assay to identify potential drugs aimed at this target. However, whether this technology bared any fruit is unclear.

In June 2006, AZ announced that its "genomic approach to anti-bacterials is yielding its first candidates". The company was referring to AZD1279, a bactericidal antibiotic from a new chemical class, which has showed good in vitro activity against resistant organisms including Streptococcus pneumoniae. AZ said at the time that the drug would enter Phase I clinical trials for respiratory infections in 2006.

The target for this drug was never disclosed however, and a spokesperson for AZ told DrugResearcher.com that the drug has now been scrapped, although she couldn't say why this decision had been taken.

Cubist Pharmaceuticals is, or at least was, interested in this target as well, having penned an academic article called 'Aminoacyl tRNA synthetases as targets for new anti-infectives' in a 1999 edition of the Federation of American Societies for Experimental Biology journal. However, again, there is no mention of this target on their website and the company was unable to confirm whether this target was still being investigated.

Why Anacor's drug seems to be enjoying success where others have failed is not known. However, it is good news for onychomycosis sufferers, the patients AN2690 aims to treat initially. It affects approximately 7 to 10 per cent of the US population, including 48 percent of those over age 70. More than 90 percent of those cases are caused by two specific fungi: Trichophyton rubrum and Trichophyton mentagrophytes. However, current treatments are limited, according to Anacor.

Existing topical treatments only succeed in 12 per cent of cases, despite sales accounting for $300m (€223m). Whereas systemic treatments are more effective (in around half of all cases), they have known toxicity. Novartis' Lamisil (terbinafine) generated sales of $978m in 2006 but the same drug has, in rare cases caused liver failure. These have resulted in the need for a transplant and even death, although the relationship between the liver problems and the drug is "uncertain", according to the drug's approved label, as the patients' involved had serious pre-existing liver conditions.

Antibiotics in failing health

By Karen Augé
Denver Post Staff Writer
The Denver Post

The last time a new tuberculosis drug was developed, Richard Nixon was in the White House and Dr. Michael Iseman was a young resident in a New York City hospital.

That drug, Rifampin, "was the biggest thing to hit TB in 30 years," said Iseman, now a doctor at National Jewish Medical and Research Center in Denver.

Since then, Iseman has become a recognized authority on TB and Rifampin has remained the centerpiece of TB treatment.

Now, however, a growing number of tuberculosis strains are not fazed by the drug - as in the highly publicized case of Andrew Speaker, who is being treated at National Jewish.

Tuberculosis isn't the only infection increasingly impervious to the antibiotics in medicine's arsenal.

In the past decade, federal agencies - such as the Centers for Disease Control and Prevention, the National Institutes of Health, and the Food and Drug Administration - have warned that antibiotic overuse has led to evolving drug-resistant bacteria.

At the same time, the agencies say, there is a dearth of research dollars for new antibiotics - creating a looming medical crisis.

"Infections that were once easily curable with antibiotics are becoming difficult, even impossible, to treat," the Infectious Disease Society of America warned in its report "Bad Bugs, No Drugs."

"The problem is dollars, not chemistry," said Christopher Spivey, a spokesman for the Boston-based Alliance for the Prudent Use of Antibiotics.

Antibiotics not as profitable

Antibiotic development requires huge investments of money, $400 million to $800 million, according to a study in the journal Clinical Infectious Diseases.

To provide as much income as drug companies get from the sale of one drug to a person who, for example, takes a weight-loss pill daily, a company would have to sell antibiotics to 200 to 500 people with an illness like pneumonia, Spivey said.

There are currently under development 50 drugs each for obesity, pain and Type II diabetes, according to PhRMA, a group representing the nation's leading drugmakers.

There are just nine new drugs in the works for tuberculosis and eight for malaria.

For staph infections and drug- resistant staph infections, PhRMA lists 23 drugs under development.

This isn't a new trend. FDA approval of new anti-bacterial drugs has dropped 56 percent in 20 years, according to a 2004 study by Brad Spellberg, a professor of medicine at the University of California, Los Angeles.

Work on new TB drugs has languished in part because of the widespread, mistaken belief that the disease was no longer a problem in this country, said Mel Spigelman, director of research and development for the Global Alliance for TB Drug Development.

Iseman said that on the world market drugmakers are discouraged from developing antibiotics.

"There is a tendency - in global use - for knock-offs," Iseman said. "Companies simply choose not to honor patent protections and it's done under the seemingly noble rubric of, 'we have patients dying of - whatever disease - in our country and we can't afford your drug, so we're going to make our own.' "

In its report, the infectious-disease society recommended incentives, such as tax breaks, for antibiotic research and development.

Difficult to draw attention

Still, drug companies don't get much public sympathy these days, which could make it politically tough for members of Congress to grant those tax breaks, Iseman said.

Antibiotic development "won't get on the radar until there is a really good killing plague," Spivey said.

In that respect, Speaker may have unintentionally done a favor for TB drug research by drawing attention to the disease, Spivey said.

Since 2000, interest in TB has picked up, said the TB Alliance's Spigelman.

While only a handful of new TB drugs are in the pipeline, even that is progress, Spigelman said.

"In 2000, we had zero," he said.

This year, the National Institutes of Health will spend $158 million on TB- drug research. The Bill and Melinda Gates Foundation has pledged $900 million over the next decade.

Four drug companies - Bayer, Novartis, AstraZeneca International and GlaxoSmithKline - now have units working on infectious diseases, including TB.

Bacteria, however, reproduce every 10 minutes or so, while it takes humans about 20 years to develop means to battle new strains, Iseman said.

"They have the ability to adapt to our drugs," he said. "So if you're in Vegas, you bet on the bugs."

Staff writer Karen Augé can be reached at 303-954-1733 or kauge@denverpost.com.



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A history of antibiotics and drug resistance
1920s-'50s: Scientists harness the power of living organisms to fight bacteria, ushering in the era of antibiotics.

1928: Scottish bacteriologist Alexander Fleming, above, accidentally discovers that a mold juice he names penicillin can kill staphylococcus bacteria.

1940: Oxford University pathologist Howard Florey isolates pure penicillin and demonstrates how it can cure a wide range of pathogens, including strep infections, gonorrhea and syphilis.

1943: Penicillin becomes the first antibiotic to be put in widespread use.

1944: Russian-born microbiologist Selman Waksman, working in the United States with soil microbiologist Albert Schatz, discovers streptomycin, a powerful antibiotic that proves effective against tuberculosis.

1958: American molecular geneticist Joshua Lederberg wins the Nobel Prize in medicine for demonstrating the way bacteria interact and exchange genetic material - a key concept behind drug resistance.

1967: The first penicillin-resistant pneumonococcal bacteria are reported in Papua New Guinea.

1968: Drug-resistant Shigella diarrhea kills 12,500 people in Guatemala.

1970-72: Penicillin-resistant gonorrhea spreads around the world, transmitted in part by U.S. servicemen, who contract the disease from prostitutes in Southeast Asia.

1976: Several weeks after attending an American Legion convention in Philadelphia, 34 people die from a mysterious form of pneumonia that thwarts available treatments and comes to be known as Legionnaires' disease.

1980s-'90s: The public-health effects of drug-resistant bacteria become clear, prompting new concerns about infectious diseases.

1986: The U.S. Food and Drug Administration, the Centers for Disease Control and Prevention, and the Department of Agriculture establish a national anti-

microbial-resistance monitoring system to track food-borne microbes.

1988-95: Studies in Finland, the Netherlands and other European countries find increased drug resistance in farm animals. Many of the livestock are fed antibiotics as growth-promoters.

1990: Puppeteer Jim Henson, creator of the Muppets, dies of toxic-shock syndrome induced by an aggressive strain of streptococcus that acts too quickly for antibiotics to work.

1992: An influx of immigrants sparks a tuberculosis epidemic in New York and other cities, forcing local officials to remobilize dormant TB prevention efforts. The federal government is spending just $55,000 a year monitoring drug resistance.

1995: A form of staph infection that is resistant to methicillin results in almost a half-billion dollars in direct medical costs and claims 1,409 lives in New York City hospitals.

1996: Japanese bacterial geneticists detect the world's first staph infection capable of resisting the powerful antibiotic vancomycin.

1997: Health officials report the percentage of antibiotic-resistant cases has surged from 2 percent in 1991 to 43 percent in 1997.

1998: The Institute of Medicine contends that overuse of antibiotics has brought about widespread drug resistance, estimating that as many as half of the prescriptions for the drugs given each year to outpatients are unnecessary. The U.S. Centers for Disease Control and Prevention spends more than $11 million a year monitoring drug resistance.

2000: The Food and Drug Administration approves one of the newest major new antibiotics, Bayer's ciprofloxacin hydrochloride, known as Cipro. Cipro makes news the following year as a treatment for a spate of unsolved anthrax poisonings.

Malta has third highest rate of antibiotic resistant infections in Europe

by Juan Ameen

A recently published European report has found that Malta has the third highest percentage of potentially deadly antibiotic-resistant hospital-acquired infections out of a list of 29 countries.

The report, which was compiled by the European Centre for Disease Prevention, found that Malta had an MRSA rate of around 55 per cent in 2005.

The study pointed out that, at present, the most important disease threat is from microorganisms that have become resistant to antibiotics. However, it went on to say that these are becoming a bigger problem outside hospitals because the microorganisms are also circulating within the community.

Romania had the highest rate of MRSA with almost 72 per cent, followed by Cyprus with around 65 per cent.

Malta came next with around 55 per cent, a slight reduction over last year’s figure of 57 per cent.

It estimated that around three million people in the EU catch a healthcare-associated infection that is fatal in around 50,000 cases.

It attributed the problem to the over-use or inappropriate use of antibiotic and anti-viral drugs, the spread of drug-resistant microbes, especially in hospitals, clinics and care centres, and a shortage of new antibiotic drugs.

“A key factor for the development of antimicrobial resistance is the amount of antibiotics used,” it said.

The study noted that detailed data on the use of antibiotics and its consumption patterns are difficult to obtain but pointed out that it is “difficult to understand why the amount of antibiotics consumed per inhabitant varies three-fold between member states.”