Effects of thiastearic acids on growth and on dihydrosterculic acid and other phospholipid fatty acyl groups of Leishmania promastigotes.
Thiastearic acid positional isomers (8, 9, 10, 11) were examined for their ability to inhibit population growth and the biosynthesis of a phosphatidylethanolamine cyclopropane fatty acyl group, cis-9,10-methyleneoctadecanoic acid (dihydrosterculic acid), by promastigotes of Leishmania species. Thiastearic acids are candidate chemotherapeutic agents, since cyclopropane fatty acids are not formed by vertebrate cells. 8- and 10-thiastearic acids strongly inhibited the growth of strains containing the most dihydrosterculic acid (Leishmania tropica and Leishmania donovani; 25-35% phosphatidylethanolamine fatty acyl groups) and less strongly inhibited strains containing no dihydrosterculic acid (Leishmania major). The 11-thiastearic acid was less effective and 9-thiastearic acid ineffective. Strains containing 1-15% dihydrosterculic acid (L. donovani, Leishmania braziliensis, Leishmania aethiopica and Leishmania mexicana mexicana) were with few exceptions not inhibited by any of the isomers. All the thiastearic acid isomers caused a dose-dependent loss of dihydrosterculic acid. This was accompanied by a loss of phosphatidylethanolamine in the case of dihydrosterculic acid-rich leishmanial strains exposed to the 8- and 10-isomers. The 8- and 10-thiastearic acids also caused a loss of C18 unsaturated fatty acyl groups and increases in palmitic and stearic acids in the phosphatidylethanolamine and phosphatidylcholine of the dihydrosterculic acid-rich and dihydrosterculic acid-free leishmanial strains. 11-Thiastearic acid was much less effective and 9-thiastearic acid ineffective. These changes were not evident in those strins which contained 1-15% dihydrosterculic acid and whose growth was not inhibited by the thiastearic acid isomers. It is concluded that thiastearic acid isomers may inhibit both dihydrosterculic acid biosynthesis and fatty acid desaturation, with the 9-isomer having the highest specificity for dihydrosterculic acid biosynthesis. Population growth of promastigotes of Leishmania species in culture is not dependent upon dihydrosterculic acid biosynthesis but is dependent upon fatty acid desaturation.
Beach
D H
DH
Department of Microbiology and Immunology, SUNY Health Science Center, Syracuse 13210.
Pascal
R A
RA
Holz
G G
GG
D000818:Animals; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D005227:Fatty Acids / Q000096:biosynthesis* / Q000378:metabolism*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013229:Stearic Acids / Q000494:pharmacology*
D005227:Fatty Acids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D013229:Stearic Acids; C050048:10-thiastearic acid; C029355:dihydrosterculic acid