Linker and Head-Group Exploration of Anti-MRSA Triaromatic Pleuromutilins
Based on hit <b>6</b>, a triaromatic pleuromutilin (TAP) and potent bacterial protein synthesis inhibitor, we explored the chemical space surrounding its pharmacophore by synthesizing 45 new conjugates. Herein, the adenine head was exchanged for new heterocycles, and the benzyl linker exchanged for aniline-, ether-, amide-, and hydroxybenzyl linkages, with all of them successfully engaging the pharmacophore, a result which was mirrored in a strict 3D pharmacophore model. The aniline- and amide-linked conjugates moreover demonstrated greater stability in liver microsomes, while especially conjugate <b>21</b>, but also <b>31</b>, <b>43</b>, <b>45</b>, and <b>55</b> displayed excellent potency, with MRSA activities on par with <b>6</b> or better. Docking to the ribosome suggested a shifted engagement with C2469 for <b>21</b> over <b>6</b>, resulting in greater multivalency, while <b>43</b>/<b>45</b> likely coordinates Mg<sup>2+</sup>. Lastly, conjugate <b>21</b> displayed efficacy equal to commercial Fucidin LEO (<b>5</b>) in a mouse <i>Staphylococcus aureus</i> skin infection model, highlighting its potential as a topical antibiotic lead.
Authors
- Louise Kamuk Storm (ORCID: https://orcid.org/0000-0001-8469-406X)
- Kristian Stærk (ORCID: https://orcid.org/0000-0003-2410-0375)
- Carsten Uhd Nielsen (ORCID: https://orcid.org/0000-0001-5776-6865)
- Janne Kudsk Klitgaard (ORCID: https://orcid.org/0000-0001-5255-2980)
- Laust Moesgaard (ORCID: https://orcid.org/0000-0002-5509-9832)
- Peter Lykke Eriksen (ORCID: https://orcid.org/0000-0003-1115-8308)
- Morten Madsen (ORCID: https://orcid.org/0000-0002-6036-8240)
- Christian Ding Fisker
- Merete Møller (ORCID: https://orcid.org/0000-0001-7514-0399)
- Amina Jega Yusuf (ORCID: https://orcid.org/0000-0002-4557-859X)
- Poul Nielsen (ORCID: https://orcid.org/0000-0001-7946-311X)
- Thomas Emil Andersen (ORCID: https://orcid.org/0000-0001-9453-1141)
- Christoffer V. Heidtmann (ORCID: https://orcid.org/0000-0002-2579-3938)
- Art Larsen
- Jens Kjølseth Møller (ORCID: https://orcid.org/0000-0002-5547-5498)
- Claus Havregaard Sørensen
- Jayappragash Ramesh
- Krista Urup
- Iben S. Højgaard
- Rasmus H. Pihlsbech
- Tore L. Rønn
- Laurits R. Caspersen
- Chris R. Sixhøj
- Sarah Løgstrup
Institutions
- University of Southern Denmark (DK)
- Odense University Hospital (DK)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- Research Research (South Africa) (ZA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00152
- Citations
- 1
- Primary Topic
- Veterinary medicine and infectious diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.35
Funders
- Hørslev-Fonden
- Innovationsfonden
- Carlsbergfondet
- Novo Nordisk Fonden