INHIBITORS OF THE D24(25) STEROL METHYLTRANSFERASE IN PARACOCCIDIOIDES BRASILIENSIS

San Blas G, Visbal G, Alvarez A, Monero B

Author address: 

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Abstract: 

The enzymes •24 (24') y •24 (25) sterol methyltransferases (SMTs) catalyze an essential step in the biosynthesis of sterols in fungi but not in vertebrates. Therefore, they are potential specific targets for antifungal therapy. In Pneumocystis carinii, the in vitro effectivity of an SMT inhibitor, 22,26-azasterol, has been proven 1 . We have studied growth inhibition in Paracoccidioides brasiliensis, by means of 22,26-azasterol and analogs. P. brasiliensis, strain Pb73, yeast phase, was plated in PYG agar, and incubated at 37º C. As inhibitors we tested: 22,26-azasterol (AZA- ), 22-piperidin-2-il-pregnan-22(S),3 -diol (AZA-2) y 22-piperidin-3-il-pregnan-22(S),3 -diol (AZA-3) between 1 0 -5 and 1 0 - 0 M. AZA- and AZA-2 were 1 00% inhibitory at concentrations of 5 x 1 0 -6 M, while AZA-3 was so at 1 x 1 0 -6 M. MIC calculations were done in liquid media 2 . Neutral lipid analysis by GC-MS showed that the main free sterol in control cells was ergosta- 5,22-dien-3 -ol (68%), followed by ergosterol (2 %) and lanosterol ( %). On exposure to either AZA 1 , 2 or 3, lanosterol accumulated (50-60%), providing evidence that the •24 (25) SMT step of sterol biosynthesis was inhibited. These results should be extended in order to explore the potential clinical use of these drugs. References 1 Urbina, J. et al., 1 997. Antimicrob. Ag. Chemother. 4 : 428- 432. 2 San-Blas, G. et al., 1 993. J. Med. Vet. Mycol. 3 : 69- 74. Acknowledgement: FONACIT, Grant S -200 000664, Caracas, Venezuela
2003

abstract No: 

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Full conference title: 

The 15 th Congress of the International Society for Human and Animal Mycology
    • ISHAM 15th (2003)