Researchers uncover structure of key protein to target in antibiotic-resistant bacteria

In the ongoing battle against antimicrobial resistance, a recent breakthrough involving researchers at the University of British Columbia and McMaster University has paved the way for the development of new drugs to treat infections that no longer respond to traditional antibiotics.

Over the last decade, the World Health Organization and governmental health organizations worldwide have repeatedly sounded the alarm about the growing threat antimicrobial resistance poses to public health. Beta-lactam antibiotics such as Penicillin, which make up the majority of prescribed antibiotic drugs, are increasingly ineffective at fighting bacterial infections. This has ushered in a challenging era of infections from resistant bacteria, such as the methicillin-resistant Staphylococcus aureus (MRSA), now widespread in clinics and communities. Without effective treatments, many people face sepsis or death.

Dr. Franco Li and Dr. Natalie Strynadka, from the University of British Columbia’s Department of Biochemistry, and their colleagues have honed in on a protein named TarL in the cell membranes of Staphylococcus aureus bacteria. This protein plays an essential role in the production of wall teichoic acid which helps bacteria cells evade the immune system and continue to spread. Using data collected at the Canadian Light Source (CLS) at the University of Saskatchewan (USask), the researchers have for the first time successfully characterized the structure of TarL in high resolution.

Membrane proteins are notoriously difficult to characterize. “By tapping into the diverse expertise within our team, we were able to solve the structure of TarL and understand how this protein works,” said Dr. Li.

The researchers used X-ray crystallographic data from the CMCF beamline at CLS in combination with cryo-EM imaging to generate a complete atomic-level “blueprint” of TarL, deepening our understanding of the protein – including potential sites to target with drugs. This detailed blueprint is instrumental in designing drugs that precisely target and block the mechanisms that allow the bacteria to proliferate.

“Microbial resistance is inevitable,” said Dr. Strynadka. “It's become clear that we need to have an arsenal of drugs to fight drug resistance now and in the future.” Developing drugs that block the function of TarL will suppress the bacteria’s pathways of infection while working synergistically with beta-lactam antibiotics in a “cocktail” treatment to improve the effect of traditional antibiotics. “This cocktail approach is increasingly prevalent in treating infections” said Strynadka.

Li and Strynadka’s pioneering work offers hope in the fight against antibiotic-resistant infections. Their team often collaborates with industry partners to test the drug targets they identify through their research and shape the design of future antibiotics.

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Li, Franco KK, Liam J. Worrall, Robert T. Gale, Eric D. Brown, and Natalie CJ Strynadka. "Cryo-EM analysis of S. aureus TarL, a polymerase in wall teichoic acid biogenesis central to virulence and antibiotic resistance." Science Advances 10, no. 9 (2024): eadj3864. https://doi.org/10.1126/sciadv.adj3864

Photos: Canadian Light Source | CMCF Beamline | Researchers / Crystals