Synthetic optimization of cystobactamids as broad-spectrum antibiotics
Creators: name: Stappert, Moritz Dominik
Publisher: name: Hannover : Institutionelles Repositorium der Leibniz Universität Hannover
Year: 2024
Subjects: subject: antibiotics
subject: cystobactamids
subject: organic chemistry
subject: Antibiotika
subject: Cystobactamide
subject: organische Chemie
subject: enthält Forschungsdaten
subject: contains research data
subject: Dewey Decimal Classification::500 | Naturwissenschaften::540 | Chemie

description: Bacterial resistance is omnipresent and expected to be a future problem as warned by the World Health Organization (WHO) reports and guidelines since 2014,[1-3] Centers for Disease Control and Prevention (CDC)[4] and European Centre of Disease Prevention and Control (ECDC)[5]. Novel scaffolds for broad-spectrum antibiotics that can displace β-lactams and quinolones are rare and their development is slow,[6] although a variety of compounds with antibacterial properties is known from nature.[7] With the cystobactamids, a highly promising antibiotic compound class was found and comprehensively expanded towards an applicable medication.[8-11] In this Thesis, the currently known library of cystobactamids was synthetically extended and the in vitro efficacy of the novel analogues was determined against various bacteria, including the highly relevant ESKAPE pathogens. Based on the current cystobactamid CN-CC 861 as lead-scaffold,[11] several new CDE-fragments were synthesized. Various highly substituted aromatic systems were synthetically accessed and implemented as ring D derivatives. These methods embrace metal-mediated aromatic functionalization, and heterocyclization among others. The cystobactamid assembly protocols were improved and simplified and applied to several new derivatives. An updated general SAR of ring D was derived by evaluating the activity test results of all new compounds. Thereby, both replacement of the hydroxy group and a rigidification between ring D and E proved difficult. Analysis of the activity against ESKAPE pathogens led to new insights into the effects of these modifications, based on which future cystobactamid analogues were targeted. A reversed amide bond between ring C and D proved to be highly advantageous here in terms of broad-spectrum activity. Novel CDE-fragments were combined with Western-fragments of the lead compound, as well as of current front-running cystobactamids. The latter included benzimidazoles, bicyclo[1.1.1]pentane and pyridin as substructures, resp. isosteres for benzene. The two most active compounds in this Thesis were part of a preclinical in vivo ADME study and will be included in follow-up trials. Besides, serine as central amino acid was found to be well tolerated and represents a more polar alternative for the central alkyl amino acid which probably has a positive effect on solubility. [1] Antimicrobial resistance: global report on surveillance, World Health Organization, 2014 [2] No time to wait: securing the future from drug-resistant infections, World Health Organization, 2019 [3] Global priority list of antibioticresistant bacteria to guide research, discovery, and development of new antibiotics, World Health Organization, 2017 [4] Antibiotic resistance threats in the United States, 2013, Centers for Disease Control and Prevention, Office of Infectious Disease., 2013 [5] Antimicrobial resistance surveillance in Europe; 2023 - 2021 data, European Centre for Disease Prevention and Control (ECDC) and World Health Organization (WHO), 2023 [6] H. W. Boucher, G. H. Talbot, J. S. Bradley, J. E. Edwards, D. Gilbert, L. B. Rice, M. Scheld, B. Spellberg, J. Bartlett, Clin. Infect. Dis. 2009, 48, 1-12. [7] M. Miethke, M. Pieroni, T. Weber, M. Brönstrup, P. Hammann, L. Halby, P. B. Arimondo, P. Glaser, B. Aigle, H. B. Bode, R. Moreira, Y. Li, A. Luzhetskyy, M. H. Medema, J.-L. Pernodet, M. Stadler, J. R. Tormo, O. Genilloud, A. W. Truman, K. J. Weissman, E. Takano, S. Sabatini, E. Stegmann, H. Brötz-Oesterhelt, W. Wohlleben, M. Seemann, M. Empting, A. K. H. 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, M. Graz, M. Lindvall, S. Ramurthy, A. Karlén, M. van Dongen, H. Petkovic, A. Keller, F. Peyrane, S. Donadio, L. Fraisse, L. J. V. Piddock, I. H. Gilbert, H. E. Moser, R. Müller, Nat. Rev. Chem. 2021, 5, 726-749. [8] S. Baumann, J. Herrmann, R. Raju, H. Steinmetz, K. I. Mohr, S. Hüttel, K. Harmrolfs, M. Stadler, R. Müller, Angew. Chem., Int. Ed. 2014, 53, 14605-14609. [9] G. Testolin, K. Cirnski, K. Rox, H. Prochnow, V. Fetz, C. Grandclaudon, T. Mollner, A. Baiyoumy, A. Ritter, C. Leitner, J. Krull, J. van den Heuvel, A. Vassort, S. Sordello, M. M. Hamed, W. A. M. Elgaher, J. Herrmann, R. W. Hartmann, R. Müller, M. Brönstrup, Chem. Sci. 2020, 11, 1316-1334. [10] T. Seedorf, Doctoral thesis, LUH 2023. [11] D. Kohnhäuser, Doctoral thesis, LUH 2021.