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. 1986 Jan;29(1):33–39. doi: 10.1128/aac.29.1.33

Hydrophobic polyoxins are resistant to intracellular degradation in Candida albicans.

H A Smith, P Shenbagamurthi, F Naider, B Kundu, J M Becker
PMCID: PMC180359  PMID: 3524423

Abstract

Two novel polyoxins, N-epsilon-(octanoyl)-lysyl-uracil polyoxin C (Oct-Lys-UPOC) and N-gamma-(octyl)-glutaminyluracil polyoxin C (Oct-Gln-UPOC), were synthesized by reacting uracil polyoxin C with the appropriate amino acid p-nitrophenyl ester. Oct-Lys-UPOC and Oct-Gln-UPOC were strong inhibitors (Kis = 1.7 X 10(-6)M) of chitin synthetase from Candida albicans membrane preparations. In a permeabilized-cell assay, Oct-Gln-UPOC had a 10-fold-lower inhibitory activity toward chitin synthetase than did the Oct-Lys-UPOC analog. Both compounds were resistant to hydrolysis by a cell extract of C. albicans H317; however, Oct-Gln-UPOC was hydrolyzed with a half-life of 23 min by a permeabilized-cell preparation. Oct-Lys-UPOC was resistant to hydrolysis by permeabilized cells. Oct-Gln-UPOC and Oct-Lys-UPOC did not compete with the transport of peptides or uridine into the cell. At concentrations up to 2 mM these two new polyoxins were ineffective in the inhibition of cell growth or reduction of cell viability, but they induced aberrant morphologies in C. albicans at a concentration of 0.25 mM. These data suggest that polyoxins containing hydrophobic amino acids retain strong chitin synthetase inhibitory activity and are resistant to cellular hydrolysis. They provide the first example of effective synthetic chitin synthetase inhibitors which are stable inside C. albicans.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Azuma T., Saita T., Isono K. Polyoxin analogs. III. Synthesis and biological activity of aminoacyl derivatives of polyoxins C and L. Chem Pharm Bull (Tokyo) 1977 Jul;25(7):1740–1748. doi: 10.1248/cpb.25.1740. [DOI] [PubMed] [Google Scholar]
  2. Becker J. M., Covert N. L., Shenbagamurthi P., Steinfeld A. S., Naider F. Polyoxin D inhibits growth of zoopathogenic fungi. Antimicrob Agents Chemother. 1983 Jun;23(6):926–929. doi: 10.1128/aac.23.6.926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cabib E., Roberts R., Bowers B. Synthesis of the yeast cell wall and its regulation. Annu Rev Biochem. 1982;51:763–793. doi: 10.1146/annurev.bi.51.070182.003555. [DOI] [PubMed] [Google Scholar]
  4. Emmer G., Ryder N. S., Grassberger M. A. Synthesis of new polyoxin derivatives and their activity against chitin synthase from Candida albicans. J Med Chem. 1985 Mar;28(3):278–281. doi: 10.1021/jm00381a003. [DOI] [PubMed] [Google Scholar]
  5. Fernandez M. P., Correa J. U., Cabib E. Activation of chitin synthetase in permeabilized cells of a Saccharomyces cerevisiae mutant lacking proteinase B. J Bacteriol. 1982 Dec;152(3):1255–1264. doi: 10.1128/jb.152.3.1255-1264.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Lee K. L., Buckley H. R., Campbell C. C. An amino acid liquid synthetic medium for the development of mycelial and yeast forms of Candida Albicans. Sabouraudia. 1975 Jul;13(2):148–153. doi: 10.1080/00362177585190271. [DOI] [PubMed] [Google Scholar]
  7. Logan D. A., Becker J. M., Naider F. Peptide transport in Candida albicans. J Gen Microbiol. 1979 Sep;114(1):179–186. doi: 10.1099/00221287-114-1-179. [DOI] [PubMed] [Google Scholar]
  8. Medoff G., Brajtburg J., Kobayashi G. S., Bolard J. Antifungal agents useful in therapy of systemic fungal infections. Annu Rev Pharmacol Toxicol. 1983;23:303–330. doi: 10.1146/annurev.pa.23.040183.001511. [DOI] [PubMed] [Google Scholar]
  9. Mehta R. J., Kingsbury W. D., Valenta J., Actor P. Anti-Candida activity of polyoxin: example of peptide transport in yeasts. Antimicrob Agents Chemother. 1984 Mar;25(3):373–374. doi: 10.1128/aac.25.3.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mitchell L. H., Soll D. R. Commitment to germ tube or bud formation during release from stationary phase in Candida albicans. Exp Cell Res. 1979 Apr;120(1):167–179. doi: 10.1016/0014-4827(79)90547-0. [DOI] [PubMed] [Google Scholar]
  11. Naider F., Shenbagamurthi P., Steinfeld A. S., Smith H. A., Boney C., Becker J. M. Synthesis and biological activity of tripeptidyl polyoxins as antifungal agents. Antimicrob Agents Chemother. 1983 Nov;24(5):787–796. doi: 10.1128/aac.24.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Shenbagamurthi P., Smith H. A., Becker J. M., Steinfeld A., Naider F. Design of anticandidal agents: synthesis and biological properties of analogues of polyoxin L. J Med Chem. 1983 Oct;26(10):1518–1522. doi: 10.1021/jm00364a030. [DOI] [PubMed] [Google Scholar]
  13. Yadan J. C., Gonneau M., Sarthou P., Le Goffic F. Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases. J Bacteriol. 1984 Dec;160(3):884–888. doi: 10.1128/jb.160.3.884-888.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]

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