Abstract:
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.
Authors: Johnson JW, Ellis MJ, Piquette ZA, MacNair C, Carfrae L, Bhando T, Ritchie NE, Saliba P, Brown ED, Magolan J.
Reference: ACS Med. Chem. Lett. 2022 January 21; doi: 10.1021/acsmedchemlett.1c00648