The current lead compounds demonstrate potent antibacterial activity against a broad range of pathogens, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter spp, Acinetobacter baumannii, Stenotrophomonas maltophilia and Pseudomonas aeruginosa – including the pandrug-resistant isolates where there are currently no treatment options available.
The potent in vitro activity has also been demonstrated in vivo. Significantly, the compounds have shown both potent in vitro and in vivo activity towards colistin-resistant isolates (colistin is considered as the treatment of last resort against Gram-negative ESKAPE pathogens).
Antibiotics of the OMPTA class combine high-affinity binding to both Lipopolysaccharide (LPS) and outer membrane proteins, resulting in high specificity towards Gram-negative bacteria and effective bactericidal activity. The video shows the LPS export mechanism by LptD-LptE which is inhibited by murepavadin.
Video Source: Dr. Kerstin Moehle, University of Zurich
Bacteria species grouped under the term “Gram-negative” (as they do not retain a stain developed by the Danish researcher Hans-Christian Gram) are of particular concern as they are especially well protected by an inner and outer membrane from the action of antibiotics. Gram-negative bacteria are a common cause of serious and often life-threatening infections including intra-abdominal infections, urinary tract infections, pneumonia and bacteremia (blood stream infections).
Polyphor started developing its innovative chemistry (“macrocycle”) platform more than a decade ago, resulting in a leading position in this emerging drug class. An important part of this platform and source of the novel antibiotics are macrocyclic “Protein Epitope Mimetics” (PEM), medium-sized (0.7-2 kDa), fully synthetic, cyclic peptide-like molecules that mimic secondary structures of proteins.
Polyphor’s PEM antibiotics form a new class: the Outer Membrane Protein Targeting Antibiotics (OMPTA). They are characterized by a low rate of resistance development and offer new treatment options for patients with difficult-to-treat infections caused by Gram-negative bacteria (including multidrug resistant or “MDR” strains).
Antibiotics of the OMPTA class combine high-affinity binding to both LPS and outer membrane proteins, resulting in high specificity towards Gram-negative bacteria and efficient bactericidal activity.
While Murepavadin is highly selective for Pseudomonas aeruginosa, the latest novel “PEM antibiotics” exhibit broad-spectrum activity against Gram-negative bacteria, amongst them Escherichia coli and bacteria belonging to ESKAPE.
In addtion to the “PEM antibiotics”, Polyphor is progressing the development of the new thanatin derivatives, which may lead to another family of compounds inhibiting the outer membrane assembly of Gram-negative pathogens through a different mechanism than other OMPTAs developed so far. The first program is targeting specifically Enterobacteriaceae including multidrug resistant strains.
- Outer Membrane Protein Targeting Antibiotics (OMPTA): a novel class of antibiotics discovered at Polyphor
- Highly efficacious towards a large panel of MDR-isolates of Gram-negative ESKAPE pathogens, including strains resistant to colistin (note: colistin is an antibiotic often considered as the last option for treatment of MDR Gram-negative bacteria)
- Favorable safety profile in animals
- Favorable resistance profile compared to known antibiotics
- Excellent activity in animal systemic infection models
“Chimeric peptidomimetic antibiotics against Gram-negative bacteria”, published on Nature, October 2019 (PDF)
“Protein epitope mimetic macrocycles as biopharmaceuticals”, published on Sciencedirect.com, June 13, 2016 (PDF)
Overall, the OMPTA display an extremely promising broad and potent coverage against Gram-negative bacteria species belonging to the difficult-to-treat ESKAPE pathogens. So far, there has been very low cross-resistance observed with comparator antibiotics. OMPTA seem to overcome colistin resistance in all of the tested ESKAPE pathogens, including K. pneumoniae, well known to overproduce capsule polysaccharides (CPS) which serve as a protective shield and limit the killing effect of current antibiotics. No activity is observed against Gram-positive bacteria.
The University of Zurich and Polyphor have been awarded a grant from the Swiss Commission of Technology and Innovation (CTI; project CTI-Nr.: 181146.1 PFLS; Swiss Government). The joint research focuses on expanded studies on the mechanism of action of the new class of antibiotics against Gram-negative ESKAPE pathogens. The project started in January 2016 and was supervised jointly by Prof. John A. Robinson and Dr. Daniel Obrecht and has successfully completed in July 2018. The project has been supported by the Wellcome Trust foundation and is now being supported by Novo Holdings A/S with an investment of up to CHF 11.5 million.
In February 2019 Polyphor has been awarded a non-dilutive award of up to $5.6 million from CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) to support the development of a novel OMPTA candidate until the completion of the Phase I clinical trial. The OMPTA candidate addresses the deadliest and most resistant Gram-negative bacterial pathogens, including those designated as a critical concern by the World Health Organization.
In May 2019 Polyphor received an award from Innosuisse to accelerate the development of a new class of antibiotics, the antimicrobial peptide thanatin. The new antibiotic which is being developed in collaboration with the University of Zurich, inhibits the lipopolysaccharide (LPS) transport pathway.
The search for broad-spectrum antibiotics was built upon applying the PEM technology to discover novel peptidomimetics targeting a broad range of important Gram-negative pathogens. Polyphor currently plans to focus on a new formulation for POL7306 and peptide design optimization for other candidates to achieve broader therapeutic margins before moving into clinical trials.
Besides POL7306, Polyphor initiated a program wiht thanatin, targeting specifically Enterobacteriaceae including multidrug resistant strains, one of the most common and resistant strains.