Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery Journal Articles uri icon

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  • Metergoline is a semisynthetic ergot alkaloid identified recently as an inhibitor of the Gram-negative intracellular pathogen Salmonella Typhimurium (S. Tm). With the previously unknown antibacterial activity of metergoline, we explored structure-activity relationships (SARs) with a series of carbamate, urea, sulfonamide, amine, and amide analogues. Cinnamide and arylacrylamide derivatives show improved potency relative to metergoline against Gram-positive bacteria, and pyridine derivative 38 is also effective against methicillin-resistant Staphylococcus aureus (MRSA) in a murine skin infection model. Arylacrylamide analogues of metergoline show modest activity against wild-type (WT) Gram-negative bacteria but are more active against strains of efflux-deficient S. Tm and hyperpermeable Escherichia coli. The potencies against WT strains of E. coli, Acinetobacter baumannii, and Burkholderia cenocepacia are also improved considerably (up to >128-fold) with the outer-membrane permeabilizer SPR741, suggesting that the ergot scaffold represents a new lead for the development of new antibiotics.


  • Johnson, Jarrod W
  • Ellis, Michael J
  • Piquette, Zoë A
  • MacNair, Craig
  • Carfrae, Lindsey
  • Bhando, Timsy
  • Ritchie, Nikki E
  • Saliba, Paul
  • Brown, Eric
  • Magolan, Jakob

publication date

  • February 10, 2022