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Chemistry Nobel Prize Brings Future Of Antibiotics Into Focus

Chemistry Nobel Prize Brings Future Of Antibiotics Into Focus

Examining the award-winning work toward the future of antibiotics that won the 2009 Nobel Prize in chemistry.

Thursday, October 8, 2009 - 14:15

Jason Socrates Bardi, Editor

(Inside Science) -- When the Nobel Prize committee announced its chemistry prize on Wednesday, they highlighted the relevance of the award-winning work toward the future of antibiotics -- a future that may not be so far away.

One of the winners is biochemist Thomas Steitz from Yale University in New Haven, Conn. Steitz is deeply involved with a Connecticut company that has already completed the first two phases of clinical trials on a potent new antibiotic that was designed based on the award-winning research. If a third and final clinical trial phase concludes successfully, the company expects to submit a new drug application to the U.S. Food and Drug Administration in 2012.

Steitz, who shared the prize with Venkatraman Ramakrishnan of the U.K. and Ada E. Yonath of Israel, was recognized for his role in uncovering the mechanistic secrets of a core of biological molecules known as ribosomes, which are massive blobs of proteins and genetic material that play a key role in all biological organisms -- from humans to horseflies to bacteria.

During Wednesday's hastily-organized press conference in New Haven, Conn., Steitz described how this molecule works. "The ribosome is the translator," he said. 

What it does is make proteins, the crucial enzymes and building blocks of cells, from bits of genetic information derived from the DNA genes within a cell. This critical late stage in the process of gene expression is so essential to life that within any given cell, there may be thousands of ribosomes churning away.

Steitz recalled when the ribosome structure was finally pieced together several years ago and he first peered into the inner workings of this massive molecular machine. He said it was one of the most exhilarating moments in his scientific career. 

Nothing as large and as complicated as the ribosome had ever been tackled using X-ray crystallography, a standard technique in biology that helps scientists determine the atomic structures of molecules. The ribosome is the largest complex molecule solved using this technique.

The research stretched over two decades and had to surmount many technological barriers before finally coming to fruition at the turn of the century, when the two big pieces of the ribosome were first fully described by groups led by Steitz and Ramakrishnan. Their structures showed in great detail how various parts of the ribosome fit together, and it answered the question of how this massive molecular machine worked.

The structures also suggested new ways for scientists to develop new antibiotic drugs or improve existing ones. In awarding the prize yesterday, the Nobel committee focused the recognition particularly on that aspect of the work. 

A TARGET FOR ANTIBIOTICS

Because the ribosome is so essential for all life, including bacteria, blocking its action can be lethal. That's exactly how a large number of antibiotics on the market today work. 

"Most of the antibiotics that are out there that have been discovered since [Alexander] Fleming in the 1920s turn out to inhibit ribosome function," said Peter Moore, a biochemist at Yale University who has collaborated with Steitz for years, including on the Nobel Prize-winning work. 

Many antibiotics bind to different parts of ribosome molecules, Moore explained. This gums up their works and prevents them from making proteins. When bacteria lose the ability to churn out proteins, they often die. What makes such antibiotics particularly effective is the fact that they specifically attack ribosomes in bacteria but leave human ribosomes alone. This means that people can generally take them without serious side effects.

Structures, like those solved by Steitz, Moore, and their colleagues, can help guide further drug development efforts by showing scientists where to throw new sand in the ribosome's gears.

In the years since the original ribosome structures were solved, Steitz and Moore have worked out more than two dozen additional structures of the ribosome with different antibiotics bound to them -- work that has revealed how certain strains of bacteria can evolve to grow resistant to bacteria, which is one of the biggest emerging threats to public health worldwide.

"It's easy for us to forget how lethal bacterial are and how terrible they were for our grandparents," said Moore. 

DRUGS UNDER DEVELOPMENT

Several years ago, Steitz and Moore co-founded and joined the scientific advisory board of a small drug company in Connecticut that is currently developing the next generation of antibiotics aimed at combating drug-resistant bacteria based on structures like those that they began unraveling a decade ago. 

The company has a number of compounds in development, including one that targets the ribosome. The compound is a potential broad-spectrum treatment that works similar to the drug Zyvox, an antibiotic that is currently used for treating a variety of bacteria that cause pneumonia and skin infections -- including drug-resistant strains.

Though the new compound is not currently on the market, it has just completed a Phase II clinical trial that showed positive results in treating a number of different bacterial infections in 160 people. The next big step before the company can submit an application for FDA approval will be to complete a Phase III trial, which will test the compound in thousands of people.

Using biological structures to develop new drugs is not a new approach, said University of North Carolina at Chapel Hill biochemist Charles Carter, an expert in X-ray crystallography who was not involved in any of the Nobel-winning research. Structural biology has long held the promise of helping scientists rationally design drugs.

Carter said that about 15 years ago there was excitement in pharmaceutical companies after structure-based approaches proved invaluable for designing the first generation of HIV protease inhibitors -- a powerful class of HIV/AIDS drugs that began reaching the market in the mid-1990s. 

However, Carter added that there have only been a small number of drugs that have been designed this way to date. For the most part, large pharmaceutical companies continue to employ X-ray crystallographers, but often in supporting roles -- not to guide the overall design.

Whether a new generation of small pharmaceutical companies can succeed using a structure-based approach remains to be seen. But given the progress of the clinical trials by the company that Steitz and Moore co-founded, the answer may be apparent in just a few years.

 

Antibiotics that Target the Ribosome - Source: U.S. Food and Drug Administration  

Tetracyclines (doxycycline, minocycline, tetracycline)

Pleuromutilins [Altabax, (tiamulin and valnemulin -veterinary use)]

Macrolides (erythromycin, clarithromycin)

Lincosamides (lincomycin -veterinary use, clindamycin)

Everninomycins (none commercially available)

Oxazolidinones (linezolid)

Aminoglycosides (gentamicin, tobramycin, amikacin, kanamycin)

Telithromycin (Ketek)

Tylosin (veterinary use)

Spectinomycin

 

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Jason Socrates Bardi is the News Director of the American Institute of Physics and a longtime science writer.