New technique to speed up development of antibiotics

Jan Michiels: “There is a pressing need for new antimicrobial therapies in the face of increasing drug resistance. Our research shows that we can estimate the likeliness of resistance development against lead compounds, which aids the much-needed development of novel antibiotics.”

Combatting antibiotic resistance

Since the discovery of penicillin by Alexander Fleming over a century ago, antibiotics have been fundamental in modern medicine, and their use has considerably lengthened the human lifespan. Antibiotics target bacterial infections by interfering with the activity of essential bacterial proteins, often killing the bacteria. However, bacteria can acquire mutations that protect them against these medicines. The result? Antibiotic resistance, harder-to-treat infections, and increased mortality rates.

Now, researchers at the VIB- KU Leuven Center for Microbiology, together with the VIB-VUB Center for Structural Biology, show that a new technique called deep mutational scanning can predict the ease of resistance development, which helps to prioritize new protein targets for antibiotics and guide drug development.

A target for E. coli

Deep mutational scanning is a powerful method to assess the function and stability of thousands of protein variants simultaneously. By using a combination of CRISPR-based editing and high-throughput DNA sequencing, the technique can analyze the functional consequences of every possible amino acid change at each position in a protein.

In their study, the scientists used this technique to study three E. coli proteins that are essential for the bacteria’s viability and have been considered attractive targets for the development of novel antibiotics. They found that one protein, MurA, had a lower chance of developing mutations, making it the superior target for antibiotics because it is less likely to develop antibiotic resistance.

Liselot Dewachter, a postdoctoral researcher at the Michiels lab and first author of the study: “I’m very proud to present this research after years of dedication. Being able to identify which protein targets have the least chance of developing resistance is a huge step forward in the development of new antibiotics. This way, the pharmaceutical industry can focus on medication that is more likely to retain its efficacy for longer.” ​ ​

Publication

Deep mutational scanning of essential bacterial proteins can guide antibiotic development. Dewachter, et al. Nature Communications, 2023. DOI 10.1038/s41467-023-35940-3.