PEM antibiotics

Most pharmaceutical companies have abandoned their antibiotic research in recent years resulting in a development pipeline which is almost empty. Infections with Gram-negative bacteria like Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Stenotrophomonas maltophilia or Acinetobacter baumannii thus represent an increasing threat to the healthcare system because many of these bacteria increasingly develop resistance to commonly used antibiotics.

Polyphor’s antibiotics research program has led to the discovery of a novel class of both selective and broad-band antibiotics.

The most advanced compound POL7080 is currently in clinical Phase II trials. POL7080 is highly selective and potent against Pseudomonas aeruginosa and hits a novel antibiotic target, an outer membrane protein.

In parallel, Polyphor advances its antibiotic program that aims to identify novel broad spectrum Gram-negative PEM antibiotics. Building on its expertise and insight into the role of outer membrane proteins for Gram-negative bacteria, like Pseudomonas aeruginosa, Polyphor has established this drug discovery program in collaboration with Prof. John Robinson (University of Zurich, Switzerland). This public-private collaboration is being supported by the CTI (commission for innovation and technology) over a period of three years (2016-2018). Polyphor employs advanced biochemical and genetic research technologies like photoaffinity labeling, membrane protein isolation and purification, as well as functional assays and in vitro microbiological screening. First results demonstrate the efficacy of this approach by leading to the identification of broad spectrum PEM antibiotic lead compounds. Polyphor has recently initiated the lead optimization phase as well as complementary experiments to further elucidate the role of outer membrane proteins in the mechanisms of these broad spectrum antibiotics.

CTI (commission for innovation and technology)

The CTI is supporting the research activities on this novel class of macrocycle antibiotics by funding three postdocs over a period of three years in John Robinson’s group at the University of Zurich.

The aim of the project is to deliver within the three-year time frame of the collaboration potent novel PEM antibiotics with excellent in vitro and in vivo activity against the Gram-negative ESKAPE pathogens Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Enterobacter species. The compounds should cover wild-type and clinical strains, including multidrug-resistant (such as colistin-resistant) isolates. In addition to the antibacterial activity we will also study the host-protective anti-inflammatory properties of PEM antibiotics.

The main focus of Prof. John Robinson’s group will be the characterization of the MoA, which is assumed to be unexploited and completely different from the MoA of the established antibiotic classes. Besides applying classical methods such as macromolecular synthesis studies (DNA, RNA, and protein biosynthesis), they will also apply various more recent methods to study the interaction of the antibiotics with the Gram-negative outer membrane such as super high-resolution emission depletion (STED) fluorescence microscopy along with florescent dyes to highlight membranes. In addition, the B-barrel outer membrane proteome in various ESKAPE Gram-negative bacteria will be analyzed as a prerequisite for target pull-down studies. Synthesis of enantiomers and photolabeled analogues of the lead compounds will allow us to study enantioselectivity of our antibiotics, and to carry out photoaffinity labeling studies which should help uncover the target proteins that are involved in the MoA.