4-Oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I

C. A. Langner, J. K. Lodge, S. J. Travis, J. E. Caldwell, T. Lu, Q. Li, M. L. Bryant, B. Devadas, G. W. Gokel, G. S. Kobayashi, J. I. Gordon

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Candida albicans and Cryptococcus neoformans are major causes of systemic fungal infections, particularly in patients with acquired immunodeficiency syndrome. Metabolic labeling studies revealed that these organisms synthesize a small number of N-myristoylproteins, the most prominent being 20-kDa ADP- ribosylation factors (Arfs). C. albicans Arf has ~80% identity with the essential Arf1 and Arf2 proteins of Saccharomyces cerevisiae. [3H]Myristic acid analogs with oxygen for -CH2-substitutions at C4, C6, C11, and C13 are incorporated into cellular N-myristoylproteins, phospholipids, and neutral lipids produced by these three yeasts during exponential growth at 30 °C in complex media. Analog- and organism-specific differences in the efficiency of labeling of proteins and lipid classes were observed. The effects of oxatetradecanoic acids with oxygen for -CH2- substitutions at C3-C13 on C. neoformans, C. albicans, and S. cerevisiae were assessed during mid-log phase growth at 30 °C. A single dose of 3-oxa-, 4-oxa-, 5-oxa- or 6- oxatetradecanoic acid (O3-O6, final concentration = 300 μM) was able to inhibit growth of C. neoformans in the order O4 > O5 > O3 ~ O6. The other compounds were inactive. 4-Oxatetradecanoic acid was fungicidal, producing a 10,000-fold reduction in viable cell number 1 h after administration and continued suppression of cell growth for 7 h. A clear dose response was observed over a concentration range of 100-300 μM. 4-Oxatridecanoic acid was 100-fold less potent in reducing cell viability than 4-oxatetradecanoic acid but more potent than 5-oxatridecanoic acid. O4 produced ~10-100-fold reductions in the viability of C. albicans and S. cerevisiae at 300-500 μM, respectively, whereas O5 and O6 were less active. Since N-myristoylation of the Pr55(gag) polyprotein precursor produced by human immunodeficiency virus I (HIV-I) is essential for its assembly, we also assessed the antiviral effects of 4-oxatetradecanoic acid. O4 is able to produce a 50% reduction in the replication of HIV-I in acutely infected human T-lymphocyte cell lines at a concentration of 18 μM. Together, these data suggest that (i) the position of the oxygen for methylene substitution is a critical determinant of the fungicidal activity of O4 and (ii) NMT may be an attractive therapeutic target for treating opportunistic fungal infections in patients infected with HIV-I.

Original languageEnglish
Pages (from-to)17159-17169
Number of pages11
JournalJournal of Biological Chemistry
Volume267
Issue number24
StatePublished - Jan 1 1992

Fingerprint Dive into the research topics of '4-Oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I'. Together they form a unique fingerprint.

Cite this