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Remodeled antibiotic molecules used to battle drug-resistant bacteria

Sept. 23 (UPI) -- Every year, drug-resistant strains of common bacteria cause thousands of premature deaths, and the problem is getting worse, according to researchers.

Drug-resistance has rendered many old treatments obsolete, but new classes of antibiotics have been slow to materialize. To tackle the problem, researchers at the University of California, San Francisco decided to redesign existing antibiotic molecules, instead of inventing new ones.

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Scientists described the new approach in a paper published Wednesday in the journal Nature.

"The aim is to revive classes of drugs that haven't been able to achieve their full potential, especially those already shown to be safe in humans," lead study author Ian Seiple said in a news release.

"If we can do that, it eliminates the need to continually come up with new classes of drugs that can outdo resistant bacteria. Redesigning existing drugs could be a vital tool in this effort," said Seiple, an assistant professor of pharmaceutical chemistry at the UCSF School of Pharmacy.

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Researchers tested their novel approach on a class of antibiotics called streptogramins, which, until recently, was an effective weapon against Staphylococcus aureus infections. Unfortunately, the bacteria evolved resistance to the antibiotics, forcing doctors to mostly sideline the drugs.

Streptogramins work by attacking a bacteria's ribosome, preventing the bacteria from synthesizing proteins. Staphylococcus aureus eventually grew wise to the strategy.

Now, drug-resistant strains of the bacteria produce proteins called virginiamycin acetyltransferases, or Vats, which recognize and chemically disarm the drug molecules upon entering the bacterial cell.

Like many antibiotics, streptogramins are made by tweaking naturally occurring antibiotic molecules, which are typically produced by other types of bacteria. Scientists hypothesized that additional designs change might help the antibiotic evade Vats.

Instead of augmenting streptogramin molecules, researchers decided to entirely rebuild the antibiotic. To simplify the process, they created seven molecular modules, or streptogramin prototypes, that could be further customized.

"This system allows us to manipulate the building blocks in ways that wouldn't be possible in nature," said Seiple. "It gives us an efficient route to re-engineering these molecules from scratch, and we have a lot more latitude to be creative with how we modify the structures."

Once researchers had some basic molecular building blocks to work with, they used computer models to visually understand how they might fit together and tweak them in order to create a new and effective antibiotic molecule.

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"My lab's contribution was to say, 'Now that you've got the seven pieces, which one of them should we modify and in what way?'" said study co-author James Fraser, professor of bioengineering and therapeutic sciences in the UCSF School of Pharmacy.

Visual modeling helped Seiple, Fraser and their colleagues figure out which parts of the streptogramin molecules are essential to its antibiotic qualities and which non-essential parts could be manipulated to prevent Vats interference.

Using what they learned, researchers synthesized several new streptogramin molecules and tested them against drug-resistant S. aureus in infected mice. The most promising candidate was ten times more effective than traditional streptogramin drugs.

According Seiple, the team's research can serve as a blueprint for modifying other classes of antibiotics.

"We learned about mechanisms that other classes of antibiotics use to bind to the same target," he said. "In addition, we established a workflow for using chemistry to overcome resistance to antibiotics that haven't reached their potential."

Ultimately, scientists hope that by studying the molecular mechanics of previously effective antibiotics, they can design more effective drugs.

"It's a never-ending arms race with bacteria," said Fraser. "But by studying the structures involved -- before resistance arises -- we can get an idea of what the potential resistance mechanisms will be. That insight will be a guide to making antibiotics that bacteria can't resist."

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