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Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5–8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

ABSTRACTCandida auris has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the challenging super fungus, novel benzoanilide antifungal agents were discovered by an integrated strategy of phenotypic screen, hit optimization, antifungal assays and mechanism exploration. The most promising compound A1 showed potent in vitro and in vivo efficacy against Candida auris infection. Mechanism investigation revealed that compound A1 blocked the biosynthesis of virulence factors and fungal cell walls through the inhibition of glycosylphosphatidylinositol (GPI) and GPI-anchored proteins. Thus, compound A1 represents a promising lead compound to combat drug-resistant candidiasis.

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

Abstract In this paper, we present a non-convex ℓ 2/ℓ q (0

Abstract Background Cordyceps sinensis (C. sinensis) is a famous and precious Traditional Chinese Medicine (TCM), while frequent reports of heavy metals, especially arsenic, exceeding standards in C. sinensis in recent years have raised concerns of its safety. Therefore, it is urgent for a research on heavy metals (Cu, Pb, As, Cd, Hg) in C. sinensis, of its bioaccessibility, dietary exposure estimation, arsenic speciation analysis and health risks assessment to human body. Methods Three 30 g batches of mixed wild growth C. sinensis samples were collected from Qinghai Province and each batch were divided into three parts: the whole C. sinensis, the stroma and the caterpillar body. The in vitro gastrointestinal method was used to evaluate the bioaccessibility of the heavy metals in the samples. The arsenic speciation analysis in the in vitro gastrointestinal solutions and dilute nitric acid extracted solutions were conducted using high performance liquid chromatography–inductively coupled plasma mass (HPLC–ICP-MS) method. Finally, the target hazard quotient (THQ) developed by the US EPA (1989) was used to assess the health risks of heavy metals in C. sinensis. Results The contents of Cu, Pb, Cd and Hg in the stroma were higher than those in the caterpillar body. In contrast, As was mainly found in the caterpillar body. In the whole C. sinensis, the average bio-accessibilities of Cu, Pb, As, Hg and Cd were 41.29, 40.11, 64.46, 18.91, and 81.14%, respectively. While in the caterpillar body, the corresponding bio-accessibilities values were 48.26, 42.92, 66.15, 12.86, 87.07%, respectively, and were 38.30, 30.53, 30.18, 7.46, and 82.30%, respectively in the stroma part. Different arsenic speciations of arsenite [As(III)], arsenate [As(V)] and trace amounts of methylarsonic acid [MMA] were detected. Of the total As, 8.69% was in inorganic form, which was also the major form of dissolved As. Among the extracted inorganic species, the concentrations of As(III) and As(V) were 0.56 ± 0.16 and 0.29 ± 0.06 mg kg−1, respectively. In the gastrointestinal solutions, only As(III) and As(V) could be detected; the sum content of the two species was 2.00–2.73%. The bioaccessibility target hazard quotient (BTHQ) values for Cu, Pb, As, Cd and Hg in C. sinensis were 0.0041, 0.0040, 0.5334, 0.0020 and 0.0005, respectively, all less than 1. Conclusion None of the five heavy metals in C. sinensis can be 100% absorbed by human body. The content of arsenic in C. sinensis is high, but the strong toxic inorganic arsenic accounted for only 8.69%. The heavy metals in C. sinensis presented no obvious risks to human health in a reasonable taking way.

Achyranthes bidentata Blume (AB) is a health food and a sulfur-free herbal medicine that is one of the most heavily sulfur-fumigated herbs in the marketplace. In this work, a comprehensive approach using ultra-performance liquid chromatography coupled with quadrupole time-of-flight-MS (UPLC-Q-TOF-MS) and multivariate statistical analysis was developed to identify characteristic sulfur-fumigation markers, elucidate chemical transformation mechanisms and characterize the degree of sulfur-fumigation of AB. Non-fumigated and sulfur-fumigated AB samples were compared by UPLC-Q-TOF-MS/MS analysis. Three triterpene saponins (Betavulgarosides II–IV) and two amides (Feruloyl-4-O-methyldopamine and Moupinamide) were identified as characteristic markers, which were positively correlated with two active AB components, namely oleanic acid and ferulic acid, respectively. Moreover, the extent of the sulfur-fumigation under different weight ratios of sulfur to herbal materials (1:20, 1:40, and 1:80) was analyzed based on chemical transformations and sulfur dioxide residues. Further verification showed that the ratio of 1:40 within 1 h was reasonable and efficient for herb quality preservation and assurance. This study provides a reliable sulfur-fumigation protocol for the quality control of AB and other herbs.