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 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.

Genetic and Chemical Screening Reveals Targets and Compounds to Potentiate Gram-Positive Antibiotics against Gram-Negative Bacteria

“…We performed susceptibility testing of these antibiotics in four different strains of E. coli BW25113: wild type (WT), a hyperporinated strain constitutively expressing a truncated form of the FhuA pore (WT–pore), , an efflux-deficient strain (Δ tolC ), and a hyperporinated, efflux-deficient strain (Δ tolC –pore). Both rifampicin and vancomycin are largely OM excluded as their minimum inhibitory concentrations (MICs) were ≥32-fold lower in the hyperporinated strains compared to in the wild type, while the efflux-deficient strains were no more susceptible to either antibiotic (Table ).…”

“…We began by selecting five antibiotics of different classes that are effective against Gram-positive bacteria but are ineffective against Gram-negative bacteria despite the presence of otherwise susceptible intracellular targets: rifampicin (a rifamycin), novobiocin (an aminocoumarin), erythromycin (a macrolide), vancomycin (a glycopeptide), and linezolid (an oxazolidinone). We performed susceptibility testing of these antibiotics in four different strains of E. coli BW25113: wild type (WT), a hyperporinated strain constitutively expressing a truncated form of the FhuA pore (WT−pore), 21,22 an efflux-deficient strain (ΔtolC), and a hyperporinated, efflux-deficient strain (ΔtolC−pore). Both rifampicin and vancomycin are largely OM excluded as their minimum inhibitory concentrations (MICs) were ≥32-fold lower in the hyperporinated strains compared to in the wild type, while the efflux-deficient strains were no more susceptible to either antibiotic (Table 1).…”

“…coli BW25113 (E. coli Δ tolC -pore) were generated by moving the pore, as described previously, into E. coli BW25113 and E.…”

“…Bacterial strains used in this study include E. coli BW25113, E. coli BW25113 ΔtolC (Keio collection),26 E. coli ML35 pBR322,52 S. aureus Newman, E. coli D21 (CGSC #5158),53 E. coli D22 (CGSC #5163),54 E. coli CFT073, K. pneumoniae ATCC 43816, and P. aeruginosa PAO1. The hyperporinated E. coli BW25113 (E. coli WT-pore) and hyperporinated, efflux-deficient E. coli BW25113 (E. coli ΔtolC-pore) were generated by moving the pore, as described previously,21 into E. coli BW25113 and E. coli BW25113 ΔtolC, respectively.…”

Exploring functional interplay amongst Escherichia coli efflux pumps

“…In contrast, MdfA was active when produced alone in both EKO-35 and the porinated strain, and the multiplicative effects of this pump were also higher. Simultaneously expressing mdfA and Pore=fhuA ∆C/∆4L [18]. Related to Table S6.…”