Abstract
Two nitrogenous metabolites, bacillimide (1) and bacillapyrrole (2), were isolated from the culture broth of the marine-derived actinomycete Streptomyces bacillaris. Based on the results of combined spectroscopic and chemical analyses, the structure of bacillimide (1) was determined to be a new cyclopenta[c]pyrrole-1,3-dione bearing a methylsulfide group, while the previously reported bacillapyrrole (2) was fully characterized for the first time as a pyrrole-carboxamide bearing an alkyl sulfoxide side chain. Bacillimide (1) and bacillapyrrole (2) exerted moderate (IC50 = 44.24 μM) and weak (IC50 = 190.45 μM) inhibitory effects on Candida albicans isocitrate lyase, respectively. Based on the growth phenotype using icl-deletion mutants and icl expression analyses, we determined that bacillimide (1) inhibits the transcriptional level of icl in C. albicans under C2-carbon-utilizing conditions.
Highlights
IntroductionAlgae, fungi, and protozoa can grow with acetate as the sole carbon source by using it to synthesize tricarboxylic acid (TCA) cycle intermediates in the glyoxylate cycle [1]
The glyoxylate cycle is a modified tricarboxylic acid (TCA) cycle
This cycle is composed of several TCA cycle enzymatic reactions plus two additional enzymes: isocitrate lyase (ICL), which cleaves isocitrate into glyoxylate and succinate, and malate synthase, which converts glyoxylate and acetyl-CoA to malate [2]
Summary
Algae, fungi, and protozoa can grow with acetate as the sole carbon source by using it to synthesize TCA cycle intermediates in the glyoxylate cycle [1]. This cycle is composed of several TCA cycle enzymatic reactions plus two additional enzymes: isocitrate lyase (ICL), which cleaves isocitrate into glyoxylate and succinate, and malate synthase, which converts glyoxylate and acetyl-CoA to malate [2]. The glyoxylate cycle allows microbial pathogens such as Candida albicans and Mycobacterium tuberculosis to catabolize fatty acids via their breakdown to acetyl-CoA when available simple sugars such as glucose do not exist in the host environment [3,4]. ICL has been considered a promising target for the development of antimicrobial agents since the glyoxylate cycle is absent in mammalian cells
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