Putative mycobacterial efflux inhibitors from the seeds of Aframomum melegueta.
In order to identify new putative efflux pump inhibitors that represent an appropriate target in antimycobacterial chemotherapy, nine paradol- and gingerol-related compounds (1-9) isolated from the seeds of Aframomum melegueta were assessed for their potential to inhibit ethidium bromide (EtBr) efflux in a Mycobacterium smegmatis model. Five of the compounds from A. melegueta and NMR spectroscopic data of the diketone 6-gingerdione (2) and its enolic tautomers, methyl-6-gingerol (5) and rac-6-dihydroparadol (7), are presented herein for the first time. After determination of their antimycobacterial activities and modulatory effects on the MIC of antibiotics as well as their synergistic effects in combination with antibiotics against M. smegmatis mc(2) 155, their impact on EtBr accumulation and efflux was evaluated using a microtiter plate-based fluorometric assay. The compounds exhibited moderate to weak antimycobacterial activities, and the best modulators induced a 4- to 16-fold decrease of the MICs of EtBr and rifampicin as well as a reduction of the MIC of isoniazid with fractional inhibitory concentration index values indicating synergistic activities in some cases. 6-Paradol (3), 8-gingerol (6), and rac-6-dihydroparadol (7) were the most potent EtBr efflux inhibitors in M. smegmatis mc(2) 155, displaying EtBr efflux inhibiting activities comparable to reference inhibitors.
Institute of Pharmaceutical Sciences, Department of Pharmacognosy,  Karl-Franzens University Graz , Universitätsplatz 4, 8010 Graz, Austria.
Barbara
B
Gröblacher
Veronika
V
Maier
Olaf
O
Kunert
Franz
F
Bucar
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004996:Ethidium / Q000494:pharmacology; D005233:Fatty Alcohols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects*; D019906:Nuclear Magnetic Resonance, Biomolecular; D012639:Seeds / Q000737:chemistry; D030521:Zingiberaceae / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D002396:Catechols; D005233:Fatty Alcohols; D007659:Ketones; D006139:Guaiacol; C421614:6-paradol; D004996:Ethidium; C534464:8-gingerol