Blocking bacterial pathogenicity by novel quorum sensing inhibitors for the treatment of chronic Pseudomonas aeruginosa infections

Martin Empting

Martin Empting1, Christian Schütz1, Mostafa Hamed1, Ahmed S.A. Ahmed1, Andreas M. Kany1, Katharina Rox2, Anna H.K. Hirsch1, Rolf W. Hartmann1

1Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Germany,
2Helmholtz Centre for Infection Research (HZI), Germany Email: martin.empting@helmhotlz-hips.de, +49 681-98806 2031

The antimicrobial resistance (AMR) crisis is considered to be a major healthcare challenge, which is steadily exacerbating and projected to outpace cancer as a major cause of death by 2050.[1] This “silent pandemic” urgently requires the discovery and development of novel anti- infective agents with new modes-of-action (MoA).

One critical pathogen is Pseudomonas aeruginosa (PA) that causes severe chronic lung infections in patients suffering from cystic fibrosis or bronchiectasis. This opportunistic, ubiquitous gram-negative bacterium is able to switch to the biofilm mode of life, which serves as a physical barrier to survive antibiotic treatment and host immune defense. PA develops high resistance towards antibiotics resulting in maintenance of chronic infections and high mortality of infected patients. The Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system is essential for bacterial virulence and biofilm formation rendering it a suitable drug target to block PA’s pathogenicity.[2]

By systematically probing potential target proteins within the PQS QS system, we identified innate transcriptional regulator PqsR (MvfR) as the most promising point-of-intervention.[3] Following a fragment-based approach, we discovered novel structure-divergent PqsR-targeting QS inhibitors.[4] An extensive lead generation and optimization campaign yielded candidate molecules with potent virulence-attenuating properties combined with suitable pharmacokinetics and safety profiles. Notably, our QSI synergize with aminoglycoside antibiotics in biofilm eradication in vitro as well as in reducing bacterial burden in vivo. Early (non-GLP) preclinical studies are the next steps aiming at eventually translating this unprecedented MoA into the clinics.

References
[1] M. Miethke, M. Pieroni, T. Weber, M. Brönstrup, P. Hammann, L. Halby, P. Arimondo, P. Glaser, B. Aigle, H. Bode, R. Moreira, Y. Li, A. Luzhetskyy, M. Medema, J.-L. Pernodet, M. Stadler, J. Tormo, O. Genilloud, A. Truman, K. Weissman, E. Takano, S. Sabatini, E. Stegmann, H. Brötz-Oesterhelt, W. Wohlleben, M. Seemann, M. Empting, A. Hirsch, B. Loretz, C.-M. Lehr, A. Titz, J. Herrmann, T. Jaeger, S. Alt, T. Hesterkamp, M. Winterhalter, A. Schiefer, K. Pfarr, A. Hoerauf, H. Graz, C. J. M. Graz, M. Lindvall, S. Ramurthy, A. Karlén, M. van Dongen, H. Petković, A. Keller, F. Peyrane, S. Donadio, L. Fraisse, L. Piddock, I. Gilbert, H. Moser, R. Müller, Nature Reviews Chemistry 2021, 5, 726-749.

[2] S. Wagner, R. Sommer, S. Hinsberger, C. Lu, R. W. Hartmann, M. Empting, A. Titz, Journal of Medicinal Chemistry 2016, 59, 5929.

[3] C. Schütz, M. Empting, Beilstein Journal of Organic Chemistry 2018, 14, 2627-2645.

[4] C. Schütz, D.-K. Ho, M. Hamed, A. S. Abdelsamie, T. Röhrig, C. Herr, A. M. Kany, K. Rox, S. Schmelz, L. Siebenbürger, M. Wirth, C. Börger, S. Yahiaoui, R. Bals, A. Scrima, W. Blankenfeldt, J. C. Horstmann, R. Christmann, X. Murgia, M. Koch, A. Berwanger, B. Loretz, A. K. H. Hirsch, R. W. Hartmann, C.-M. Lehr, M. Empting, Advanced Science 2021, 8, 2004369.

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