Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery

Abstract

Metergoline is a semisynthetic ergot alkaloid identified recently as an inhibitor of the Gram-negative intracellular pathogen <i>Salmonella</i> Typhimurium (<i>S.</i> 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 <b>38</b> is also effective against methicillin-resistant <i>Staphylococcus aureus</i> (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 <i>S.</i> Tm and hyperpermeable <i>Escherichia coli</i>. The potencies against WT strains of <i>E. coli</i>, <i>Acinetobacter baumannii</i>, and <i>Burkholderia cenocepacia</i> 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.