Putative Mycobacterial Efflux Inhibitors from the Seeds of <i>Aframomum melegueta</i>

Abstract

In order to identify new putative efflux pump inhibitors that represent an appropriate target in antimycobacterial chemotherapy, nine paradol- and gingerol-related compounds (<b>1</b>–<b>9</b>) isolated from the seeds of A<i>framomum melegueta</i> were assessed for their potential to inhibit ethidium bromide (EtBr) efflux in a <i>Mycobacterium smegmatis</i> model. Five of the compounds from <i>A. melegueta</i> and NMR spectroscopic data of the diketone 6-gingerdione (<b>2</b>) and its enolic tautomers, methyl-6-gingerol (<b>5</b>) and <i>rac</i>-6-dihydroparadol (<b>7</b>), 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 <i>M. smegmatis</i> mc² 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 (<b>3</b>), 8-gingerol (<b>6</b>), and <i>rac-</i>6-dihydroparadol (<b>7</b>) were the most potent EtBr efflux inhibitors in <i>M. smegmatis</i> mc² 155, displaying EtBr efflux inhibiting activities comparable to reference inhibitors