Aureobasidins:  Structure−Activity Relationships for the Inhibition of the Human MDR1 P-Glycoprotein ABC-Transporter

Abstract

Cyclic depsipeptide cyclo-[D-Hmp(1)-L-MeVal(2)-L-Phe(3)-L-MePhe(4)-L-Pro(5)-L-aIle+ ++(6)-L-MeVal(7)-L-Leu(8)-L-betaHOMeVal(9)], the antifungal antibiotic aureobasidin A (AbA), was reported to interfere with ATP-binding cassette (ABC) transporters in yeast and mammalian cells, particularly the MDR1 P-glycoprotein (Pgp), a transmembrane phospholipid flippase or "hydrophobic vacuum cleaner" that mediates multidrug resistance (MDR) of cancer cells. In a standardized assay that measures Pgp function by the Pgp-mediated efflux of the calcein-AM Pgp substrate and uses human lymphoblastoid MDR-CEM (VBL(100)) cells as highly resistant Pgp-expressing cells and the cyclic undecapeptide cyclosporin A (CsA) as a reference MDR-reversing agent (IC(50) of 3.4 microM), AbA was found to be a more active Pgp inhibitor (IC(50) of 2.3 microM). Out of seven natural analogues and 18 chemical derivatives of AbA, several were shown to display even more potent Pgp-inhibitory activity. The Pgp-inhibitory activity was increased about 2-fold by some minor modifications such as those found in the naturally occurring aureobasidins AbB ([D-Hiv(1)]-AbA), AbC ([Val(6)]-AbA), and AbD [gammaHOMeVal(9)]-AbA). The replacement of the [Phe(3)-MePhe(4)-Pro(5)] tripeptide by an 8-aminocaprylic acid or the N(7)()-desmethylation of MeVal(7) led to only a 3.3-fold decreased capacity to inhibit Pgp function, suggesting that the Pgp inhibitory potential of aureobasidins, though favored by the establishment of an antiparallel beta-sheet between the [D-Hmp(1)-L-MeVal(2)-L-Phe(3)] and [L-aIle(6)-L-MeVal(7)-L-Leu(8)-] tripeptides, does not critically depend on the occurrence of the [L-Phe(3)-L-MePhe(4)-L-Pro(5)-L-aIle(6)] type II' beta-turn secondary structure. In contrast, the most potent Pgp inhibitors were found among AbA analogues with [betaHO-MeVal(9)] residue alterations, with some data suggesting a negative impact of the [L-Leu(8)-L-betaHOMeVal(9)-D-Hmp(1)] gamma-turn secondary structure on Pgp inhibitory potential. The [2,3-dehydro-MeVal(9)]-AbA was the most potent Pgp inhibitory aureobasidin, being 13-fold more potent than AbA and 19-fold more potent (on a molar basis) than CsA. Finally, there was no correlation between the SAR for the human MDR1 Pgp inhibition and the SAR for Saccharomyces cerevisiae antifungal activity, which is mediated by an inositol phosphoceramide synthase activity.

Interactions between ABC‐transport proteins and the secondary Fusarium metabolites enniatin and beauvericin

“…ABCB1, exporting toxins back into the luminal space of the gut [35]. Consistently, several structurally related hydrophobic peptides and ionophores like valinomycin, gramicidin D, CSA [36] and aureobasidins [37,38] are known to be substrates for the human ABC transporter ABCB1. Moreover, it has been suggested previously that ENNs are substrates for the human ABCB1 functional ortholog Pdr5p in Saccharomyces cerevisiae [39].…”

Inhibitory Effect of Aureobasidin A on Toxoplasma gondii

“…Therefore, the sequence similarity may be too low to reveal a possible T. gondii IPC synthase by a homology search. Aureobasidin A has been shown to be a substrate for the human MDR1,2 P-glycoproteins (Pgp) (20,36), which are members of the ATP-binding cassette (ABC) transporter family and mediate the efflux of solutes across cell membranes. Some Pgp inhibitors, including cyclosporine A and its derivatives, were found to inhibit T. gondii replication, suggesting a possible role of Pgp in T. gondii physiology (32).…”

Development of predictive in silico model for cyclosporine- and aureobasidin-based P-glycoprotein inhibitors employing receptor surface analysis

“…1) [30] and aureobasidins (60-84, Fig. 1 and Table 1) [31] was gathered for modeling. The in vitro bioactivities of the inhibitors are expressed as the concentration of the test compound that inhibited Pgp activity by 50% (IC 50 ) in Pgp expressing multidrug resistant leukemia CEM cells.…”

“…Structure-activity relationship analyses suggested common inhibitory binding site for these inhibitors and that their activities can be improved by modifying some of their amino acid residues [29][30][31][32]. However, CsAs and AbAs are large and chemically complex molecules, which seems to have discouraged attempts to model their inhibitory structure-activity relationships.…”