Synthesis of an Antimicrobial Enterobactin‐Muraymycin Conjugate for Improved Activity Against Gram‐Negative Bacteria

• Published in: Chemistry : a European journal 2023-01, Vol.29 (5), p.e202202408-n/a
• Main Authors: Rohrbacher, Christian, Zscherp, Robert, Weck, Stefanie C., Klahn, Philipp, Ducho, Christian
• Format: Article
• Language: English
• Subjects: acetylmuramyl-pentapeptide-translocase; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibacterial agents; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria; Bacterial Proteins - metabolism; beta-lactam antibiotics; Biosynthesis; catecholate siderophore; Cell walls; Chemical Sciences; Chemistry; Conjugates; E coli; Efflux; Enterobactin; Escherichia coli - metabolism; escherichia-coli; Gram-negative bacteria; Gram-Negative Bacteria - metabolism; in-vitro; Kemi; lead structures; Membrane proteins; Microbial Sensitivity Tests; MraY; muraymycins; natural-products; nucleoside; Nucleosides; Optimization; Peptidoglycans; siderophore-drug conjugate; structural insights; Structure-Activity Relationship
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202202408

Overcoming increasing antibiotic resistance requires the development of novel antibacterial agents that address new targets in bacterial cells. Naturally occurring nucleoside antibiotics (such as muraymycins) inhibit the bacterial membrane protein MraY, a clinically unexploited essential enzyme in peptidoglycan (cell wall) biosynthesis. Even though a range of synthetic muraymycin analogues has already been reported, they generally suffer from limited cellular uptake and a lack of activity against Gram‐negative bacteria. We herein report an approach to overcome these hurdles: a synthetic muraymycin analogue has been conjugated to a siderophore, i. e. the enterobactin derivative EntKL, to increase the cellular uptake into Gram‐negative bacteria. The resultant conjugate showed significantly improved antibacterial activity against an efflux‐deficient E. coli strain, thus providing a proof‐of‐concept of this novel approach and a starting point for the future optimisation of such conjugates towards potent agents against Gram‐negative pathogens. The synthesis of a thiol‐containing muraymycin analogue and its use in an antimicrobial muraymycin‐enterobactin conjugate with an intracellularly cleavable disulfide linker is reported. This conjugation approach was shown to increase antimicrobial activity against an efflux‐deficient E. coli strain.