T4SS helps bacteria spread drug resistance genes through the formation of a pilus to exchange DNA. Credit: UT Southwestern Medical Center.
Key Points:
- For the first time, scientists determined the 3D structure of the entire T4SS complex.
- The findings provide a blueprint that could help researchers design drugs that slow the development of antibiotic resistance genes.
An international team of researchers has taken a key step forward in the fight against antibiotic resistance by elucidating the structure of the Type IV secretion system (T4SS), a protein complex on the outer envelope of bacterial cells that helps them exchange DNA with neighboring bacteria and resist antibiotics.
Scientists have long been searching for ways to shut down T4SS. This study, published in Nature, now provides a blueprint that could help researchers design drugs that slow the development of antibiotic resistance genes.
First, molecular biologists at the University of London used cryo-EM to elucidate the structure of T4SS—no small feat since the T4SS complex is larger than 99.6% of all those included to date in the worldwide library of protein structures.
Qian Cong, a computational biologist at UT Southwestern, then used her background in statistics and machine learning to analyze T4SS protein sequences from several bacteria to generate structural predictions, which were compared with the cryo-EM data. Her computational analysis supported the cryo-EM data and suggested a hypothesis about the function of T4SS. While it was already known that T4SS is involved in pilus assembly, Cong predicted how it occurs.
With that prediction in hand, researchers were able to make specific mutations within the relevant pieces of the complex and validate Cong’s hypothesis in live bacteria.
“In addition to the contribution we have made toward the development of drugs to slow the spread of antibiotic resistance genes, this study showcases the power of modern computational methods to validate experimental results and suggest functional insights beyond available experimental data,” said Cong.
Information provided by UT Southwestern Medical Center.