Abstract
Cryptococcus neoformans is an important human pathogen with limited options for treatments. We have interrogated extracts from fungal fermentations to find Cryptococcus-inhibiting natural products using assays for growth inhibition, differential thermosensitivity, and synergy with existing antifungal drugs. Extracts from fermentations of strains of Discosia rubi from eastern Texas showed anticryptococcal bioactivity with preferential activity in agar zone of inhibition assays against C. neoformans at 37°C versus 25°C. Assay-guided fractionation led to the purification and identification of chaetoglobosin P as the active component of these extracts. Genome sequencing of these strains revealed a biosynthetic gene cluster consistent with chaetoglobosin biosynthesis and β-methylation of the tryptophan residue. Proximity of genes of the actin-binding protein twinfilin-1 to the chaetoglobosin P and K gene clusters suggested a possible self-resistance mechanism involving twinfilin-1 which is consistent with the predicted mechanism of action involving interference with the polymerization of the capping process of filamentous actin. A C. neoformans mutant lacking twinfilin-1 was hypersensitive to chaetoglobosin P. Chaetoglobosins also potentiated the effects of amphotericin B and caspofungin on C. neoformans.
Highlights
Cryptococcus species are among the most common causes of invasive fungal infections globally
Semipreparative high performance liquid chromatography (HPLC) separations and HPLC-MS data were acquired on an Agilent 1260 system equipped with a diode array detector (DAD) and coupled to an Agilent 6120 single quadrupole mass spectrometer, with a binary solvent system consisting of 0.1% aqueous formic acid and 0.1% formic acid in acetonitrile
Two strains (TTI-0863 = NRRL 66951, TTI-0885 = NRRL 66952) of an unknown Discosia species were isolated from mycelium emerging from the cut end of a dead hardwood log and from mixed pine and oak forest litter at the Center for Biological Studies Field Studies, Sam Houston State University, near Huntsville, Walker Co., Texas
Summary
Cryptococcus species are among the most common causes of invasive fungal infections globally. Antifungal Chaetoglobosin P From Discosia rubi cryptococcal disease, exceeding the number due to tuberculosis. Current treatments are limited to few antifungal agents (amphotericin B, flucytosine, fluconazole), with no new therapies introduced in the past few decades. These options remain unsatisfactory because of their toxicity, inability to reliably eradicate the fungal pathogen, and the emergence of drug resistance (Brown et al, 2012; Perfect, 2017). Genome sequencing of the two producing strains has provisionally identified the chaetoglobosin P biosynthetic gene cluster (BCG) and revealed a possible mechanism of β-methylation of the tryptophan residue, leading to a biosynthetic hypothesis for chaetoglobosin P. We explored the antifungal spectrum of chaetoglobosin P in the fungal human pathogen C. neoformans, its potential mechanisms of action, and its synergy with other antifungal drugs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
