Trapping the protein servants of drug-resistant bacteria

Researchers from Belgium’s VIB, KU Leuven and UZ Leuven have devised a novel approach to developing antibacterial drugs, in a breakthrough that is set to combat the rise of antibiotic resistance.

A key contributor to antibiotic resistance is that most antibiotics today work according to only a few mechanisms of action, so when a bacterium becomes tolerant to one drug, it often becomes tolerant to the whole family. To solve this situation, scientists need to develop an entirely new class of drugs that shares no structural or mechanistic similarities with the existing antibiotics.

Professors Joost Schymkowitz and Frederic Rousseau of VIB-KU Leuven, in collaboration with Professor Johan Van Eldere of University Hospitals Leuven, have gone one step further: they have developed a new way of designing antibiotic drugs that can give rise to many new antibacterial molecules. Described in the journal Nature Communications, the drugs are designed to penetrate bacterial cells, where they induce a process called protein aggregation.

This process resembles what happens when boiling an egg, but now without heat: proteins that normally need to carry out essential functions for the bacteria — such as digesting their food — clump together and can no longer carry out their work. As this affects many proteins in the bacterial cell all at once, the bacteria rapidly succumb and die.

The scientists reveal novel molecules with a strong antibacterial (bactericidal) activity against Gram-negative bacteria. They found the approach was effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model.

The technology will now be further explored and exploited by biotech start-up Aelin Therapeutics, recently founded by VIB, KU Leuven, VUB and UGent. The company plans to use the study findings to generate many more antibacterial molecules, with the aim of targeting a wide array of diseases.

Image caption: Professor Frederic Rousseau and Professor Joost Schymkowitz.