Suvanine Sesterterpenes from a Tropical Sponge Coscinoderma sp. Inhibit Isocitrate Lyase in the Glyoxylate Cycle

Abstract

The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase (MLS). Mutants of Candida albicans lacking ICL are markedly less virulent in mice than the wild-type. Suvanine sesterterpenes (1−9) isolated from a tropical sponge Coscinoderma sp. were evaluated for their inhibitory activities toward recombinant ICL from C. albicans. These studies led to the identification of a potent ICL inhibitor, suvanine salt (2), which possesses a sodium counterion and displays an inhibitory concentration value (IC50) of 6.35 μM. The growth phenotype of ICL deletion mutants and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses indicated that compound 2 inhibits the ICL mRNA expression in C. albicans under C2-carbon-utilizing conditions. The present data highlight the potential for suvanine sesterterpenes treatment of C. albicans infections via inhibition of ICL activity.

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

“…The NMR instruments and mass spectrometry equipment have been described in a previous report [29]. HPLC analysis was conducted using the Shimadzu SCL-10A (Shimadzu, Tokyo, Japan) control system connected to the RID-10A refractive index detector (Shimadzu) and UV-Vis SPD-10A detector (Shimadzu).…”

“…The inhibitory activity of the test compound was calculated relative to that of the DMSO control ( n = 3). The methods for determination of the IC 50 value and ICL enzyme concentrations have been described in previous reports [29]. A known ICL inhibitor, 3-nitropropionate, was used as a reference control [32].…”

Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

“…The supernatant protein was estimated by Lowry method. The isocitrate lyase (ICL) enzyme assay was conducted with the isolated crude extract as described elsewhere (Lee et al 2014). The 1 ml reaction volume contained 25 mmol imidazole (pH 6Á8), 5 mmol MgCl 2 , 1 mmol EDTA, 4 mmol phenylhydrazine HCl, 1 mmol DL-isocitric acid (substrate) and cell-free extract.…”