@article{6c2525c3120746c68044c4f0c2dd86fc,
title = "Regio- and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives",
abstract = "The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram-positive pathogens and Plasmodium falciparum. Although chlorotonil shows promising activities, the scaffold is highly lipophilic and displays potential biological instabilities. Therefore, we strived towards improving its pharmaceutical properties by semisynthesis. We demonstrated stereoselective epoxidation of chlorotonils and epoxide ring opening in moderate to good yields providing derivatives with significantly enhanced solubility. Furthermore, in vivo stability of the derivatives was improved while retaining their nanomolar activity against critical human pathogens (e.g. methicillin-resistant Staphylococcus aureus and P. falciparum). Intriguingly, we showed further superb activity for the frontrunner molecule in a mouse model of S. aureus infection.",
keywords = "Anti-Infectives, Chlorotonil, Epoxidation, Natural Products, Pharmacokinetics",
author = "Walter Hofer and Emilia Oueis and Fayad, {Antoine Abou} and Felix Deschner and Anastasia Andreas and {de Carvalho}, {La{\`i}s Pessanha} and Stephan H{\"u}ttel and Steffen Bernecker and Linda P{\"a}tzold and Bernd Morgenstern and Nestor Zaburannyi and Markus Bischoff and Marc Stadler and Jana Held and Jennifer Herrmann and Rolf M{\"u}ller",
note = "Funding Information: We thank Klaus-Peter Conrad and Kathrin I. Mohr for clone production. We want to thank Rolf Jansen for the help with the large-scale fermentation of chlorotonils. We thank Kerstin Schober and Rolf Jansen for help with downstream processing after fermentation. The authors would also like to thank Sarah Karam for performing in vivo experiments. Instrumentation and technical assistance for this work were provided by the Service Center X-ray Diffraction, with financial support from Saarland University and German Science Foundation (project number INST 256/506-1). The following reagents were provided by the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) for distribution by BEI Resources, NIAID, NIH: Staphylococcus aureus subsp. aureus, strain JE2 (WT) and transposon mutants SAUSA300_0690 and SAUSA300_0691. Open Access funding enabled and organized by Projekt DEAL. Funding Information: We thank Klaus‐Peter Conrad and Kathrin I. Mohr for clone production. We want to thank Rolf Jansen for the help with the large‐scale fermentation of chlorotonils. We thank Kerstin Schober and Rolf Jansen for help with downstream processing after fermentation. The authors would also like to thank Sarah Karam for performing in vivo experiments. Instrumentation and technical assistance for this work were provided by the Service Center X‐ray Diffraction, with financial support from Saarland University and German Science Foundation (project number INST 256/506‐1). The following reagents were provided by the Network on Antimicrobial Resistance in (NARSA) for distribution by BEI Resources, NIAID, NIH: subsp. , strain JE2 (WT) and transposon mutants SAUSA300_0690 and SAUSA300_0691. Open Access funding enabled and organized by Projekt DEAL. Staphylococcus aureus Staphylococcus aureus aureus Publisher Copyright: {\textcopyright} 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",
year = "2022",
month = jul,
day = "25",
doi = "10.1002/anie.202202816",
language = "British English",
volume = "61",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "30",
}
