Expanding antibiotic chemical space around the nidulin pharmacophore

Abstract

Reinvestigating antibiotic scaffolds that were identified during the Golden Age of antibiotic discovery, but have long since been "forgotten", has proven to be an effective strategy for delivering next-generation antibiotics capable of combatting multidrug-resistant superbugs. In this study, we have revisited the trichloro-substituted depsidone, nidulin, as a selective and unexploited antibiotic lead produced by the fungus Aspergillus unguis. Manipulation of halide ion concentration proved to be a powerful tool for modulating secondary metabolite production and triggering quiescent pathways in A. unguis. Supplementation of the culture media with chloride resulted in a shift in co-metabolite profile to dichlorounguinols and nornidulin at the expense of the non-chlorinated parent, unguinol. Surprisingly, only marginal enhancement of nidulin was observed, suggesting O-methylation may be rate-limiting. Similarly, supplementation of the media with bromide led to the production of the corresponding bromo-analogues, but also resulted in a novel family of depsides, the unguidepsides. Unexpectedly, depletion of chloride from the media halted the biosynthesis of the non-chlorinated parent compound, unguinol, and redirected biosynthesis to a novel family of ring-opened analogues, the unguinolic acids. Supplementation of the media with a range of unnatural salicylic acids failed to yield the corresponding nidulin analogues, suggesting the compounds may be biosynthesised by a single polyketide synthase. In total, 12 new and 11 previously reported nidulin analogues were isolated, characterised and assayed for in vitro activity against a panel of bacteria, fungi and mammalian cells, providing a comprehensive structure-activity profile for the nidulin scaffold.

Classification of Aspergillus, Penicillium, Talaromyces and related genera (Eurotiales): An overview of families, genera, subgenera, sections, series and species

“…Extrolites : Aspergillus unguis produces asperunguisones (and 3-ethyl-5,7-dihydroxy-3,6-dimethyl phthalide), penicillin G, unguinols (= nidulins), aspergillusidones, aspergicides, agonodepsides, emeguisins, folipastatins, haiderin, nasrin, rubidin, shirin, yasimin (= unguinol = tridechloronidulin), unguisins, unguispyrones, ustilaginoidin C and violaceols / orcinols ( Chen et al., 2016a , Phainuphong et al., 2017a , Morshed et al., 2018 , Phainuphong et al., 2018a ), while A . croceus produces desertorins / kotanins and sterigmatocystin and A .…”

Antibacterial and Cytotoxic Phenolic Polyketides from Two Marine-Derived Fungal Strains of Aspergillus unguis

“…It has been recognized that A. unguis is a producer of phenolic polyketides (depsides and depsidones of nidulin derivatives) using orsellinic acid (18), and aspergillusphenol A (17) as building blocks. Some compounds, such as nidulin (7), nornidulin (8), unguinol (5), and agonodepside A (13) were repeatedly isolated from different strains of A. unguis as major secondary metabolites (SMs) [5][6][7]. During our study on NPs from marine-derived fungi, we isolated two fungal strains IV17-109 and 158SC-067, which were identified as Aspergillus unguis by ITS gene sequencing.…”

“…The positive Cotton effects observed at 305 nm (band IV) and 375 nm (band II) in the ICD spectrum of 12 suggested the absolute configuration of C-2″ as 2″R (Figures 3 and S24). Thus, the structure of 12 was determined as agonodepside B glyceride and named agonodepside C. The structures of the known compounds were determined as decarboxyunguidepside A (2) [7,10], 2-chlorounguinol (4) [6], unguinol (5) [11,12], 3,1 -dichlorounguinol (6) [13], nidulin (7) [11], nornidulin (8) [11], aspergillusidone B (9) [14], aspersidone (10) [11], agonodepside B (11) [5], agonodepside A (13) [5], guisinol (14) [4], folipastatin (15) [11], emeguisin A ( 16) [11], and aspergillusphenol A ( 17) [8] by comparing their spectroscopic data with those reported in the literature.…”

“…Aspergillus unguis is well known as a producer of numerous phenolic polyketides, which showed various pharmacological activities such as antibacterial, antifungal, cytotoxic, and antioxidant activities [4][5][6][7][8]. As part of our ongoing studies to discover new marine NPs with biological activities, the crude extracts from two strains of A. unguis IV17-109 and 158SC-067 showed good antibacterial activity and have been chemically investigated.…”

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

“…As part of our investigations into expanding the chemical space around the “lost antibiotic” nidulin and its related fungal natural products [ 25 ], our team recently reported the semisynthesis and in vitro biological evaluation of thirty-four derivatives of the parent fungal depsidone antibiotic, unguinol [ 26 ]. Fifteen first-generation unguinol analogs were synthesized and screened against a panel of bacteria, fungi, and mammalian cells to formulate a basic structure–activity relationship for the unguinol pharmacophore.…”