ABSTRACT
Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.
Subject(s)
Anti-Bacterial Agents/pharmacology , Berberine/pharmacology , Flavonoids/pharmacology , Plants, Medicinal/chemistry , Silymarin/analogs & derivatives , Staphylococcus aureus/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Biological Transport/drug effects , Drug Synergism , Ethidium/metabolism , Fluorescence , Humans , Membrane Potentials , Models, Biological , Molecular Structure , Multidrug Resistance-Associated Proteins , Staphylococcus aureus/pathogenicityABSTRACT
Three trace alkaloids from Colorado blue spruce, Picea pungens, were identified by synthesis and GC-MS comparisons as 4alpha-hydroxy-cis-2-methyl-6-(2-oxopropyl)piperidine (1), 4alpha-hydroxy-cis-2-methyl-6-propylpiperidine (11), and 1-methylgranatanone (15) (N-methyl-9-aza-1-methylbicyclo[3.3. 1]nonane or N-methyleuphococcinine). Alkaloids 1 and 11 are the first among numerous known pine and spruce piperidines to contain a ring-oxygenated substituent.
Subject(s)
Alkaloids/isolation & purification , Piperidines/isolation & purification , Trees/chemistry , Alkaloids/chemistry , Hydroxylation , Magnetic Resonance Spectroscopy , Mass Spectrometry/methods , Piperidines/chemistryABSTRACT
A new alkaloid, isothalisopavine, was isolated from Thalictrum minus and shown to be 2,3,8-trimethoxy-7-hydroxyisopavine from spectral evidence. The known thalisopavine, from T. dasycarpum, is 2,3,8-trimethoxy-9-hydroxyisopavine. Isothalisopavine is the first of its class to be substituted unsymmetrically in the two aromatic rings.
