Friday 18 December 2020

Synthetic antibiotic outmanoeuvres resistant bacteria


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.


Microbiologists 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. The scientists 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.




Qi Li, Jenna Pellegrino, D. John Lee, Arthur A. Tran, Hector A. Chaires, Ruoxi Wang, Jesslyn E. Park, Kaijie Ji, David Chow, Na Zhang, Axel F. Brilot, Justin T. Biel, Gydo van Zundert, Kenneth Borrelli, Dean Shinabarger, Cindy Wolfe, Beverly Murray, Matthew P. Jacobson, Estelle Mühle, Olivier Chesneau, James S. Fraser, Ian B. Seiple. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature, 2020; DOI: 10.1038/s41586-020-2761-3


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

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