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Home>news>Big News>Customizable synthetic antibiotic outmaneuvers resistant bacteria

Customizable synthetic antibiotic outmaneuvers resistant bacteria

Sep 24 2020 share:

Antibiotic resistance is one of the world's most urgent public health threats. In the United States alone, tens of thousands of deaths result each year from drug-resistant strains of common bacteria such as Staphylococcus aureus and Enterococcus faecium, which can cause virtually untreatable hospital-acquired infections. Perilously few new classes of antibiotics are being developed to fight infections that have become resistant to traditional treatments, and bringing any new drugs to market could take decades.                                                                                          

Researchers at UC San Francisco are tackling antibiotic resistance using a different approach: redesigning existing antibiotic molecules to evade a bacterium's resistance mechanisms. By devising a set of molecular LEGO pieces that can be altered and joined together to form larger molecules, the researchers have created what they hope is the first of many "rebuilds" of drugs that had been shelved due to antibiotic resistance. The research was published September 23, 2020, in 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," said Ian Seiple, Ph.D., an assistant professor in the UCSF School of Pharmacy's Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute (CVRI), and lead author on the paper. "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."

In work descibed in the new Nature paper, Seiple and his collaborator James Fraser, Ph.D. a professor in the School of Pharmacy's Department of Bioengineering and Therapeutic Sciences in the UCSF School of Pharmacy, have demonstrated this approach with a class of antibiotics called streptogramins. Until recently, streptogramins were very effective against S. aureus infections, until the bacteria evolved a clever resistance mechanism.

Streptogramins disable bacteria by gumming up the works in the bacterial ribosome, making it impossible for the bacteria to make proteins. But bacteria resistant to streptogramins produce proteins called virginiamycin acetyltransferases (Vats), which recognize these antibiotics when they enter the bacterial cell. The Vats grab the drug and chemically deactivate it before it can bind to the ribosome, rendering it useless.

Streptogramins, like most other antibiotics, are derived from naturally occurring antibiotic compounds produced by other organisms (usually bacteria) that are then tweaked to optimize their performance in the human body. Seiple figured that there must also be a way to make further changes to the drug molecule that would allow it to evade capture by the Vat proteins.


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