Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6-phosphate synthase.
The mechanism of anticandidal action of novel synthetic dipeptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) residues was shown to be consistent with the "warhead delivery" concept. FMDP dipeptides were shown to be transported into Candida albicans cells by the di-tripeptide permease and subsequently hydrolyzed by intracellular peptidases, especially aminopeptidase. The anticandidal activity of the particular FMDP dipeptide was influenced by the rate of its transport and, to a lower extent, by the intracellular cleavage rate. A high transport rate accompanied by a high cleavage rate resulted in the high anticandidal activity of L-norvalyl-FMDP. The strong growth-inhibitory effect of this compound was the consequence of inhibition of the enzyme glucosamine-6-phosphate synthase by the released FMDP. The action of L-norvalyl-FMDP on exponentially growing C. albicans cells resulted in a sharp decrease of incorporation of 14C label from [14C]glucose into chitin, mannoprotein, and glucan. This effect, as well as the growth-inhibitory effect, was fully reversed by exogenous N-acetyl-D-glucosamine. Glucosamine-6-phosphate synthase was proved to be the only essential target for FMDP dipeptides. Scanning electron microscopy of C. albicans cells treated with L-norvalyl-FMDP revealed highly distorted, wrinkled, and collapsed forms. Cells formed long, bulbous chains, and partial lysis occurred.
Milewski
S
S
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdańsk, Poland.
Andruszkiewicz
R
R
Kasprzak
L
L
Mazerski
J
J
Mignini
F
F
Borowski
E
E
D001692:Biological Transport; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D005650:Fumarates / Q000493:pharmacokinetics / Q000494:pharmacology*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors*; D007424:Intracellular Fluid / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D004151:Dipeptides; D005650:Fumarates; C068215:norvalyl-N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid; D015091:beta-Alanine; C056276:N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)