Senkyunolide B exhibits broad‐spectrum antifungal activity against plant and human pathogenic fungi via inhibiting spore germination and destroying the mature biofilm

Abstract

BackgroundAspergillus infection seriously jeopardize the health and safety of life of immunocompromised patients. The emergences of antifungal resistance highlight a demand to find new effective antifungal drugs. Angelica sinensis is a medicine–food herb and phthalides are its characteristic components. A few of phthalides have been reported to display satisfactory antifungal activities against plant pathogenic fungi. However, the structure activity relationships and antifungal action mechanism of phthalides remain to be further explored and elucidated.ResultsThe antifungal activities of five natural phthalides and four artificial analogues were investigated, and their structure activity relationships were preliminarily elucidated in current study. The benzene ring moiety played an essential role in their antifungal activities; the oxygen‐containing substituents on the benzene ring obviously impact their activities, the free hydroxyl was favorable to the activity. Typical phthalide senkyunolide B (SENB) exhibited broad antifungal activities against human and plant pathogenic fungi, especially, Aspergillus fumigatus. SENB affected the spore germination and hyphae growth of A. fumigatus via downregulating phosphatidylinositol‐PKC‐calcineurin axis and the expression of ENG genes. Moreover, SENB disturbed the oxidation‐reduction process in A. fumigatus to destroy the mature biofilms. In vivo experiments indicated SENB significantly prolonged survival and decreased fungal burden in mouse model of invasive pulmonary aspergillosis.ConclusionsPhthalides could be considered as the valuable leads for the development of antifungal drug to cure plant and human disease.This article is protected by copyright. All rights reserved.

Discovery of Antifungal Norsesquiterpenoids from a Soil-Derived Streptomyces microflavus: Targeting Biofilm Formation and Synergistic Combination with Amphotericin B against Yeast-like Fungi

“…Antibacterial and antifungal tests were performed in Luria–Bertani and RPMI-1640 broth, respectively. The experimental procedures were performed as described in our previous studies. , Test compounds were dissolved in DMSO and 2-fold serially diluted to different concentrations. 100 μL of suspensions containing 1 × 10 6 cfu/mL of bacteria (2 × 10 3 cfu/mL for fungi) and 1 μL test sample solutions were added to each well of 96-well microtiter plates, and the final concentration of test compound was 200, 100, 50, 25, 12.5, 6.25, 3.13 μg/mL, respectively.…”

“…As a continuous effort on searching for new structurally diverse norsesquiterpenoids from streptomycete, the secondary metabolites of Streptomyces microf lavus (YIM 31470) were investigated. Targeting a series of blue or violet spots on TLC led to the isolation of thirty-five norsesquiterpenoids including twenty-two new compounds, ( 4 S , 4 a S , 7 R , 8 a S ) -7 -h y d r o x y -1 -o x o g e o s m i n ( 1 ) , (4S,4aS,6R,8aS)-6-hydroxy-1-oxogeosmin (2), (2S,4S,4aS, 8aR)-2-hydroxy-8-oxogeosmin (3), (4S,4aS,8aR)-8-oxogeosmin (4), (4R,4aS,6R,8aR)-6-hydroxy-3-oxogeosmin (5), (2S,4S,4aR,5S,6R,8aR)-2-hydroxy-5,6-epoxy-4a-deoxygeosmin (10) geosmin (11), 2α,6β-dihydroxy-4a-deoxygeosmin (12), 3β,6βdihydroxy-4a-deoxygeosmin (13), 1α,6α-dihydroxy-4a-deoxygeosmin (14), 4α,6β-dihydroxy-4a-deoxygeosmin (15), (1S,4R,4aR,7R)-1,7-dihydroxy-trinoreremophilene (16), 6αhydroxygeosmin (17), 1β,3β-dihydroxygeosmin (18), 2β,6βdihydroxygeosmin (19), 6β,8α-dihydroxygeosmin (20), 1β,8αdihydroxygeosmin (21), 3β,8α-dihydroxygeosmin (22), 3β,7αdihydroxygeosmin (23), 3β,6β-dihydroxygeosmin (24), 4α,6βdihydroxygeosmin (25), 1β,4α-dihydroxygeosmin (26) as well as 13 known analogues 6−9, 27−35. The structures of new norsesquiterpenoids 1−5, 10−26 were determined by detailed spectroscopic data analysis including experimental and calculated ECD data.…”

“…+ , 237.1462). 6β,8α-Dihydroxygeosmin(20). Colorless oil; [α] D 20 = −33 (c 0.24, MeOH); IR (film) ν max 3704, 2973, 2941, 2867, 1456, 1369, 1055, 1030, 1012 cm −1 ; 1 H and 13 C NMR see Tables 5 and 4; HRESIMS m/z: 237.1460 [M + Na] + (calcd for C 12 H 22 NaO 3 + , 237.1462).…”

Design, synthesis and bioactivity of a new class of antifungal amino acid‐directed phthalide compounds

“…Butylidenephthalide and butylphthalide, senkyunolide B are all antifungal substances extracted from plants that contain basic skeletons of phthalide. 16 Phthalide compounds have good antifungal activity, and its hazard code is Xi (Irritant), with rarely reported toxicity. 17 Therefore, phthalide can be chosen as a lead compound.…”

“…Therefore, when designing and synthesizing target compounds, it is important to consider how to reduce toxicity and simplify synthesis steps while maintaining activity. Butylidenephthalide and butylphthalide, senkyunolide B are all antifungal substances extracted from plants that contain basic skeletons of phthalide 16 . Phthalide compounds have good antifungal activity, and its hazard code is Xi (Irritant), with rarely reported toxicity 17 .…”