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

Chemistry

Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123, Saarbrücken, Germany.

Published: January 2023

AI Article Synopsis

  • Antibiotic resistance is increasing, necessitating the creation of new antibacterial agents that target specific functions in bacteria.
  • Naturally occurring nucleoside antibiotics like muraymycins inhibit a crucial enzyme (MraY) involved in bacterial cell wall synthesis but struggle with cellular uptake and effectiveness against Gram-negative bacteria.
  • Researchers developed a synthetic muraymycin analog linked to a siderophore (Ent), enhancing its entry into Gram-negative bacteria and demonstrating improved antibacterial activity, paving the way for future optimization of such compounds.

Article Abstract

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 Ent , 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10107792PMC
http://dx.doi.org/10.1002/chem.202202408DOI Listing

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