Inhibitors of Bacterial Multidrug Efflux Pumps from the Resin Glycosides of Ipomoea murucoides

Abstract

A reinvestigation of the CHCl 3-soluble extract from flowers of the Mexican medicinal arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded six new pentasaccharides, murucoidins VI-XI (1- 6), as well as the known pescaprein III (7), stoloniferin I (8), and murucoidins I-V (9- 13). Their structures were characterized through the interpretation of their NMR spectroscopic and FABMS data. Compounds 1-6 were found to be macrolactones of three known glycosidic acids identified as simonic acids A and B, and operculinic acid A, with different fatty acids esterifying the same positions, C-2 on the second rhamnose unit and C-4 on the third rhamnose moiety. The lactonization site of the aglycone was placed at C-2 or C-3 of the second saccharide unit. The esterifying residues were composed of two short-chain fatty acids, 2-methylpropanoic and (2S)-methylbutyric acids, and two long-chain fatty acids, n-dodecanoic (lauric) acid and the new (8R)-(-)-8-hydroxydodecanoic acid. For the latter residue, its absolute configuration was determined by analysis of its Mosher ester derivatives. All members of the murucoidin series exerted a potentiation effect of norfloxacin against the NorA overexpressing Staphylococcus aureus strain SA-1199B by increasing the activity 4-fold (8 microg/mL from 32 microg/mL) at concentrations of 5-25 microg/mL. Stoloniferin I (8) enhanced norfloxacin activity 8-fold when incorporated at a concentration of 5 microg/mL. Therefore, this type of amphipathic oligosaccharide could be developed further to provide more potent inhibitors of this multidrug efflux pump.

Characterization of a xylose containing oligosaccharide, an inhibitor of multidrug resistance in Staphylococcus aureus, from Ipomoea pes-caprae

“…In addition to the results previously reported for other lipophilic oligosaccharides, e.g., the murucoidins (Chérigo et al, 2008(Chérigo et al, , 2009 and orizabins (Pereda-Miranda et al, 2006b), the susceptibility of Staphylococcus aureus to the non-cytotoxic pescapreins (1-9) seems to correlate to the acylation degree of the oligosaccharide core. The lipophilic properties would seem to be an important structural requirement to facilitate cellular uptake to its MDR pump target.…”

“…This 14 mass unit difference was also observed for all common fragment peaks produced by glycosidic cleavage of each sugar moiety at m/z 1005, 823, 531, and 403 in compound 1. This compound exhibited the initial loss of two esterifying groups at m/z 1151 [MÀHÀC 5 H 8 O] À and 1053 [MÀHÀC 12 H 22 O] À which represented the elimination of one unit of a-methylbutyric acid and one of dodecanoic acid, respectively (Chérigo et al, 2008;Escobedo-Martínez and Pereda-Miranda, 2007;Pereda-Miranda et al, 2005).…”

“…Convolvulaceous oligosaccharides have been shown to exert a potentiation effect of norfloxacin against the NorA over-expressing Staphylococcus aureus strain SA-1199B (Chérigo et al, 2008(Chérigo et al, , 2009Pereda-Miranda et al, 2006b). They have demonstrated good activity at low concentrations (10 mM or less) being more active than reserpine, a known efflux pump inhibitor used as a reference control.…”

Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria

“…Several compounds, such as reserpine, behave as if they inhibit efflux pumps and hence have become known as efflux pump inhibitors (EPIs) [4]. Since that time, numerous phytochemicals have been shown to have activity against S. aureus or other Grampositive bacteria, or to act as potential EPIs with antimicrobials for Gram-positive bacteria [5][6][7][8][9][10][11]. Unfortunately, most of the plant-derived compounds have little or no activity with antibiotics against Gram-negative bacteria and it was suggested that, as many plant pathogens are Gram-negative bacteria, plants may not produce molecules effective against these organisms [5].…”

Resin glycosides from the leaves and stems of Ipomoea digitata

“…Among them, 3-5 were identified as murucoidin XI [7], murucoidin IV [8], and quamoclin IV [9], respectively, based on their physical and spectroscopic data (Fig. 1).…”