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.

Molecular replacement for small-molecule crystal structure determination from X-ray and electron diffraction data with reduced resolution

“…Yet, firstly, it still can represent a sufficiently 'good' initial search model; secondly, we have seen several examples in the field of natural products where the conformation of large molecular fragments is almost entirely preserved in different environments or is similar despite different side groups. The examples are given by chelocardin, having a rigid core fragment (Les ˇnik et al, 2015), argyrin, demonstrating practically the same configuration of the polypeptide cyclic part within the crystal structure, in solution and in a protein complex (Gorelik et al, 2022), and chlorotonil A and chlorotonil B, containing different side groups, but preserving the conformation of the macrocycle (Gerth et al, 2008;Jungmann et al, 2015;Hofer et al, 2022).…”

β-Lactams from the Ocean

“…Culture of the chlorotonil-producing myxobacterium Sorangium cellulosum on a >150 L scale secured multi-gram quantities of chlorotonil. Its chemical stabilization (by reductive mono-dechlorination) followed by bis-epoxidation (to improve the water solubility to 16 µM) gave structure 2b-Epo, retaining essentially the full breadth of biological activities [ 64 ]. Structure 2b-Epo has in vitro MIC values of <0.05 mg·L −1 against several Gram-positive bacteria (including an MIC 90 of 0.1 mg·L −1 against methicillin-resistant S. aureus ), oral safety in mice at 50 mg·kg −1 attaining serum concentrations above the MIC for the activity for 24 h, and efficacy in the S. aureus mouse neutropenic thigh infection assay at i.v.…”

“…Structure 2b-Epo has in vitro MIC values of <0.05 mg·L −1 against several Gram-positive bacteria (including an MIC 90 of 0.1 mg·L −1 against methicillin-resistant S. aureus ), oral safety in mice at 50 mg·kg −1 attaining serum concentrations above the MIC for the activity for 24 h, and efficacy in the S. aureus mouse neutropenic thigh infection assay at i.v. 2 × 5 mg·kg −1 dosing [ 64 ]. Its mechanism is not yet known.…”

Back in Person: Frontiers in Medicinal Chemistry 2023

“…Besides broad antibacterial activity, these compounds display antimalarial properties. Semisynthetic derivatization, enabled by supply of chlorotonil through fermentation, led to the identification of improved derivatives which are now in preclinical development [55] …”

“…Semisynthetic derivatization, enabled by supply of chlorotonil through fermentation, led to the identification of improved derivatives which are now in preclinical development. [55] The session continued with a contribution from Gerald Platzer from MAG-Lab, who presented a workflow for studying protein-drug interactions in solution using NMR and selective isotopic labelling of proteins. By these means, nonpolar CÀ H interactions upon ligand binding can be observed.…”