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D1*

PqsR inverse agonists for adjunctive treatment of chronic respiratory infections by Pseudomonas aeruginosa including NCFB

Dr Martin Empting, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Ahmed S. A. Ahmed, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Mostafa Hamed, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Christian Schütz, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Christine K. Maurer, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Thomas Hesterkamp, Helmholtz Centre for Infection Research (HZI) & German Center for Infection Research (DZIF); Dr Ahmed A. M. Kamal, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Teresa Röhrig, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Jörg Haupenthal, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Samir Yahiaoui, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Dr Michael Zender, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS); Prof. Rolf W. Hartmann, Helmholtz Institute f. Pharmaceutical Research Saarland (HIPS)

Ascenion GmbH


Challenge

Patients suffering from chronic respiratory conditions including CF, NCFB and COPD are frequently infected by Pseudomonas aeruginosa (PA). Both, early eradication and long term suppression therapy with systematical and/or inhaled antibiotics are indicated.


Technology

Using a fragment-based and structure-informed medicinal chemistry approach we have identified small molecule inverse agonists of the PqsR (MvfR) receptor. These have been characterized in a panel of assays and models as lead compounds with anti-virulence properties. We were able to demonstrate virulence attenuating properties including the following endpoints: reduction in pyocyanin, reduction in PQS autoinducer molecule levels, reduction in PA elastase activity, reduction in lectin expression, reduced biofilm integrity and eDNA content, synergistic effect with tobramycin in eradicating bacterial biofilms. Assay-dependent IC50 values range from 0.05 to 0.5 µM. Advanced compounds were taken into mouse PK studies via the intratracheal administration route with a view to further optimize pulmonary exposure and retention. Using a mucoid PA clinical isolate, short term respiratory infection experiments in mice revealed potent on-target effect and a beneficial outcome for our compounds in monotherapy.


Commercial Opportunity

In case of our primary indication (non-cystic fibrosis bronchiectasis), we estimate an annual market potential of $150M.


Development Status

The project is in the late lead optimization phase and will enter into preclinical development by the end of the year.


Patent Situation

A patent protecting composition of matter has been filed in July 2018 (EP18181475).


Further Reading

[1] S. Wagner, R. Sommer, S. Hinsberger, C. Lu, R. W. Hartmann, M. Empting, A. Titz, J. Med. Chem. 2016, 59, 5929.

[2] C. Schütz, Empting, Beilstein J Org Chem. 2018, 14, 2627-2645.


 

PqsR inverse agonists for adjunctive treatment of chronic respiratory infections by Pseudomonas aeruginosa including NCFB