Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery.
Jarrod W JohnsonMichael J EllisZoë A PiquetteCraig R MacNairLindsey CarfraeTimsy BhandoNikki E RitchiePaul SalibaEric D BrownJakob MagolanPublished in: ACS medicinal chemistry letters (2022)
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.
Keyphrases
- escherichia coli
- gram negative
- multidrug resistant
- methicillin resistant staphylococcus aureus
- acinetobacter baumannii
- wild type
- drug resistant
- structure activity relationship
- molecular docking
- staphylococcus aureus
- klebsiella pneumoniae
- biofilm formation
- small molecule
- pseudomonas aeruginosa
- silver nanoparticles
- listeria monocytogenes
- soft tissue
- molecular dynamics simulations
- candida albicans
- high throughput
- water soluble