Inhibitory Effects of Diketopiperazines from Marine-Derived Streptomyces puniceus on the Isocitrate Lyase of Candida albicans

Abstract

The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase, and plays an important role in the pathogenesis of microorganisms during infection. An icl-deletion mutant of Candida albicans exhibited reduced virulence in mice compared with the wild type. Five diketopiperazines, which are small and stable cyclic peptides, isolated from the marine-derived Streptomyces puniceus Act1085, were evaluated for their inhibitory effects on C. albicans ICL. The structures of these compounds were elucidated based on spectroscopic data and comparisons with previously reported data. Cyclo(L-Phe-L-Val) was identified as a potent ICL inhibitor, with a half maximal inhibitory concentration of 27 μg/mL. Based on the growth phenotype of the icl-deletion mutants and icl expression analyses, we demonstrated that cyclo(L-Phe-L-Val) inhibits the gene transcription of ICL in C. albicans under C2-carbon-utilizing conditions.

New Peptides from The Marine-Derived Fungi Aspergillus allahabadii and Aspergillus ochraceopetaliformis

“…In a similar assay, compound 2 showed weak inhibition (IC 50 = 104.3 μM) of isocitrate lyase (ICL) derived from C. albicans . The IC 50 value of compound 2 is comparable to the previously reported diketopiperazine cyclo( l -Phe- l -Val) (IC 50 = 109.5 μM) isolated from marine-derived Streptomyces puniceus [22].…”

Inhibitory Effects of Epipolythiodioxopiperazine Fungal Metabolites on Isocitrate Lyase in the Glyoxylate Cycle of Candida albicans

“…The antifungal activity of secoemestrin C ( 1 ), dethiosecoemestrin ( 2 ), emestrin ( 3 ), and emestrin B ( 4 ) was evaluated against C. albicans strains (SC5314, ATCC10231, ATCC10259, ATCC11006, and ATCC18804) using a previously documented procedure [ 33 ]. The growth of C. albicans was monitored in YNB broth with glucose or potassium acetate as the carbon source.…”

Virulence and Biofilms As Promising Targets in Developing Antipathogenic Drugs Against Candidiasis

“…Isocitrate lyase (ICL) and maltate synthase are the key enzymes involved in the Glyoxylate cycle. During host infection, pathogenic microorganisms such as Aspergillus fumigatus, Magnaporthe grisea, Burkholderia pseudomallei, Mycobacterium tuberculosis and C. albicans cause upregulation of the glyoxylate cycle [139,140]. In particular, the icl gene of C. albicans is strongly activated when cells are exposed to macrophages [137].…”

“…Research has shown that disruption of icl gene rendered C. albicans unable to utilise acetate, ethanol or oleic acid. It has also been found that ICL is crucial for the survival of C. albicans in response to macrophage engulfment [137][138][139].…”

“…As this cycle does not exist in mammalian cells, ICL appears to be a prospective target for the development of antifungal drugs [127,[138][139][140]. Several inhibitors of ICL, including 3-nitropropionate, 3-bromopyruvate, 3phosphoglycerate, mycenon, oxalate and itaconate, have been identified [141].…”