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

• 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(KL), 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.

Subject headings

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Keyword

enterobactin

Gram-negative bacteria

MraY

muraymycins

siderophore-drug conjugate

acetylmuramyl-pentapeptide-translocase

beta-lactam antibiotics

natural-products

in-vitro

catecholate siderophore

nucleoside

antibiotics

antibacterial activity

structural insights

escherichia-coli

lead structures

Chemistry

Publication and Content Type

ref (subject category)

art (subject category)