ALLSCHWIL & ZÜRICH, Switzerland—Polyphor AG and the University of Zurich (UZH) have announced a publication in Nature that describes the discovery and characterization of a new class of Gram-negative antibiotics covering all priority 1 WHO/ESKAPE pathogens, including multi-resistant (MDR), extensively resistant (XDR) and colistin-resistant bacterial strains.
According to the World Health Organization (WHO), Gram-negative bacteria like Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae that are resistant to the carbapenem and cephalosporin antibiotics pose a growing threat to human health, sometimes causing severe and often life-threatening infections. The last new class of antibiotics to reach the market against these microorganisms, the fluoroquinolones, dates back to the 1960s.
This new class of antibiotics, the Outer Membrane Protein Targeting Antibiotics (OMPTA), constitutes a potential major breakthrough in the fight against antimicrobial resistance, which is a global threat to human society and to health care systems world-wide. The new class has a unique spectrum of activity and mechanism of action. By disrupting outer membrane synthesis, the antibiotics effectively kill Gram-negative bacteria.
The paper, entitled “Chimeric peptidomimetic antibiotics against Gram-negative bacteria,” describes the results of a major joint academic and industrial effort combining researchers at the University of Zurich, University of Basel, Biozentrum, Eidgenössische Technische Hochschule and Polyphor, which uncovered the mechanism of action of the new OMPTA class.
According to the paper, “These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria.”
“So far no clinical antibiotics target these key proteins, which is an unprecedented way of specifically combating life-threatening infections caused by Gram-negative bacteria,” said Prof. John Robinson at the University of Zurich department of Chemistry, who co-headed the study.
BamA is the main component of the so-called ß-barrel folding complex (BAM), which is essential for outer membrane synthesis. After targeting this essential outer membrane protein, the antibiotics destroy the integrity of the bacterial membranes and the cells burst. The outer membrane of Gram-negative bacteria protects the cells from toxic environmental factors, such as antibiotics, and is also responsible for the uptake and export of nutrients and signaling molecules.
"Despite its critical importance, so far no clinical antibiotics target these key proteins required for outer membrane biogenesis," Robinson added.
“Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo,” the article explains. “The lead candidate is currently in preclinical toxicology studies that—if successful—will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.”
“We are proud to have discovered a novel class of antibiotics potentially addressing a major unmet medical need. We are grateful to acknowledge the invaluable support and contributions of our academic partners and would also like to mention the financial support from CTI/Innosuisse, Wellcome Trust (WT), CARB-X, and the Novo REPAIR Impact Fund,” noted Daniel Obrecht, chief scientific officer at Polyphor and co-head of the work. “POL7306, a first lead molecule of the novel antibiotics class, is now in preclinical development.”