Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics

• Published in: European journal of medicinal chemistry Vol. 188; p. 112005
• Main Authors: Grandclaudon, Charlotte, Birudukota, N.V. Suryanarayana, Elgaher, Walid A.M., Jumde, Ravindra P., Yahiaoui, Samir, Arisetti, Nanaji, Hennessen, Fabienne, Hüttel, Stephan, Stadler, Marc, Herrmann, Jennifer, Miethke, Marcus, Hartmann, Rolf W., Müller, Rolf, Hirsch, Anna K.H., Brönstrup, Mark
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2020; Elsevier
• Subjects: Antibiotics; Chelocardin; Chemistry, Medicinal; Gram-negative bacteria; Life Sciences & Biomedicine; Natural product; Pharmacology & Pharmacy; Science & Technology; Semisynthesis; Tetracycline; Natural product; Semisynthesis; Gram-negative bacteria; Antibiotics; Chelocardin; Tetracycline; PALLADIUM; PRIMARY TARGET; NATURAL-PRODUCTS; CHLORIDES; CATALYST; TETRACYCLINE ANALOGS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.112005

To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C–C coupling reactions. The antibacterial activity of the reaction products was tested against a panel of Gram-positive and Gram-negative pathogens. The emerging structure–activity relationships (SARs) revealed that positions C7 and C10 are favorable anchor points for the semisynthesis of optimized derivatives. The observed SAR was different from that known for tetracyclines, which underlines the pronounced differences between the two compound classes. [Display omitted] •Semi-synthesis study of the novel antibiotic amidochelocardin at four positions.•Amidochelocardin is amenable to methylation, acylation, electrophilic substitution and oxidative C–C coupling reactions.•Positions C7 and C10 are anchor points for optimized derivatives with gram-negative activity.•SAR is different from tetracyclins, reflecting different mechanisms of action.