New antibiotics effective against Gram-negative bacteria

Swiss researchers have discovered a new class of antibiotics with what is claimed to be a unique spectrum of activity and mechanism of action — a major step in the fight against antimicrobial resistance. By disrupting outer membrane synthesis, the antibiotics effectively kill Gram-negative bacteria.

According to the World Health Organization, Gram-negative bacteria like Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae, which are resistant to the carbapenem and cephalosporin antibiotics, pose a growing threat to human health, as they can cause severe and often life-threatening infections. The last new class of antibiotics to reach the market against these microorganisms dates back to the 1960s; novel antibiotics with new mechanisms of action against Gram-negative bacteria are therefore urgently needed.

Swiss researchers headed by the University of Zurich (UZH) and pharmaceutical company Polyphor, a former UZH start-up, have now reported the discovery and characterisation of a new family of synthetic antibiotics that possess broad-spectrum anti-Gram-negative antimicrobial activity. The results of their work have been published in the journal Nature.

“The new antibiotics interact with essential outer membrane proteins in Gram-negative bacteria,” said John Robinson from the UZH Department of Chemistry, who co-headed the study. “According to our results, the antibiotics bind to complex fat-like substances called lipopolysaccharides and to BamA, an essential protein of the outer membrane of Gram-negative bacteria.”

BamA is the main component of the so-called ß-barrel folding complex (BAM), which is essential for outer membrane synthesis. The outer membrane of Gram-negative bacteria has the important function of protecting the cells from toxic environmental factors, such as antibiotics, and is also responsible for the uptake and export of nutrients and signalling molecules.

“Despite its critical importance, so far no clinical antibiotics target these key proteins required for outer membrane biogenesis,” said Robinson.

That has all changed with the discovery of the new class of antibiotics, which target BamA and destroy the integrity of the bacterial membrane, causing the bacterial cells to burst. Polyphor now plans to progress one of the new compounds into human clinical trials.

“POL7306, a first lead molecule of the novel antibiotics class, is now in preclinical development,” said Daniel Obrecht, Chief Scientific Officer at Polyphor and co-head of the work.

Image caption: E. coli cells treated with a novel chimeric peptidomimetic antibiotic. Cells in blue are alive while green cells are already killed by the peptidomimetic. Image credit: Matthias Urfer, UZH.

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