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Scientists re-engineer antibiotic to counter drug resistance

By Wai Lang Chu , 09-Feb-2006

Scientists have re-engineered a well-known antibiotic to counter drug resistance forming a new molecule in the process that could assist in treating hospital infections, which were previously resistant to common antibiotics putting its use under the spotlight.

"The continued rise of vancomycin-resistant infection poses a serious threat to hospital patients in the US and around the world," said Dale Boger of the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology.

"These infections not only increase the length of hospital stays, but they raise patient mortality rates as well. Our successful synthesis of a molecular structure that restores much of the drug's binding ability could potentially lead to the development of a new generation of antibiotics that could prove far more effective against vancomycin-resistant infections than what is available today."

 

In the study, scientists replaced a single atom from the molecular structure of vancomycin aglycon, a glycopeptide antibiotic that attacks the bacteria by inhibiting cell wall synthesis, increasing the drug's spectrum of activity.

 

The scientists then developed two different re-engineered antibiotics and compared them in an antimicrobial assay against VanA, a strain of the bacteria that is highly resistant to treatment by glycopeptide antibiotics, including vancomycin and teicoplanin (a newer drug similar to vancomycin).

 

Both showed a significant increase in binding ability-roughly 40 times more potent than today's version of the drug.

 

The actual re-engineering required not only a detailed molecular level understanding of the origin of the vancomycin resistance but a total of 24 sequential chemical steps to prepare the new antibiotics.

 

In this case, a single atom in vancomycin was altered to counter an analogous single atom change in the bacterial cell wall that accounts for the resistance.

 

The results, Boger said, suggested that no matter how the VRE altered the cell wall component, it was still sensitive to treatment by the re-engineered vancomycin analogues.

 

"The continued rise of vancomycin-resistant infection poses a serious threat to hospital patients in the US and around the world," Boger said.

 

"These infections not only increase the length of hospital stays, but they raise patient mortality rates as well. Our synthesis of a novel vancomycin analogue with a molecular structure that restores much of the drug's binding ability could potentially lead to the development of a new generation of antibiotics that could prove far more effective against vancomycin-resistant infections than what is available today," he added.

 

The most common strains of VRE-called VanA and VanB-are both capable of inhibiting the antibiotic's ability to bind to the bacteria to such a degree that the loss of antimicrobial activity is reduced nearly 1,000 fold.

 

While several antibiotics target a bacterium's cell wall, vancomycin binds to a specific component of this wall. Drug resistance results when the VRE actually alters these cell-wall components, interfering with the drug's ability to bind to the bacterium.

 

Pharma's response to the growing threat has been positive, with 2005 seeing the launch of the first in a new class of antibiotics, the glycylcyclines from Wyeth. The product, tigecycline (Tygacil) joins the oxazolidinones, (Pfizer's linezolid) and lipopeptides (Cubist's daptomycin) in a small but growing arsenal against drug-resistant bacterial infections.

 

More are expected to join the fray, with several promising drug candidates in late stage development.

 

According to PharmaprojectsPLUS, the antibiotics market was worth nearly $24 billion (€20 billion) in 2004.

 

Growth to 2009 is expected to be flat, as the market adjusts to the impact of key patent expiries and changes in prescribing patterns, there are still opportunities available, particularly in the hospital setting, where the problem is at its most serious.