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Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model 1 . Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers 2 – 6 . Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually 7 , 8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids 9 . A study reports the development of a structural derivative of amphotericin B with broad antifungal activity in mice but without the renal toxicity associated with amphotericin B.

The global spread of multidrug-resistant pathogenic fungi presents a serious threat to human health, necessitating the discovery of antifungals with unique modes of action 1 . However, conventional activity-based screening for previously undescribed antibiotics has been hampered by the high-frequency rediscovery of known compounds and the lack of new antifungal targets 2 . Here we report the discovery of a polyene antifungal antibiotic, mandimycin, using a phylogeny-guided natural-product discovery platform. Mandimycin is biosynthesized by the mand gene cluster, has evolved in a distinct manner from known polyene macrolide antibiotics and is modified with three deoxy sugars. It has demonstrated potent and broad-spectrum fungicidal activity against a wide range of multidrug-resistant fungal pathogens in both in vitro and in vivo settings. In contrast to known polyene macrolide antibiotics that target ergosterol, mandimycin has a unique mode of action that involves targeting various phospholipids in fungal cell membranes, resulting in the release of essential ions from fungal cells. This unique ability to bind multiple targets gives it robust fungicidal activity as well as the capability to evade resistance. The identification of mandimycin using the phylogeny-guided natural-product discovery strategy represents an important advancement in uncovering antimicrobial compounds with distinct modes of action, which could be developed to combat multidrug-resistant fungal pathogens. Mandimycin, a polyene macrolide, exhibits strong antifungal activity and possesses a mode of action that is distinct from other compounds of this class.

Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT-1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed.

Pink biofilms are multispecies microbial communities that are commonly found in moist household environments. The development of this pink stain is problematic from an aesthetic point of view, but more importantly, it raises hygienic concerns because they may serve as a potential reservoir of opportunistic pathogens. Although there have been several studies of pink biofilms using molecular analysis and confocal laser scanning microscopy, little is known about the spatial distributions of constituent microorganisms within pink biofilms, a crucial factor associated with the characteristics of pink biofilms. Here we show that Raman spectroscopic signatures of intracellular carotenoids and polyenes enable us to visualize pigmented microorganisms within pink biofilms in a label-free manner. We measured space-resolved Raman spectra of a pink biofilm collected from a bathroom, which clearly show resonance Raman bands of carotenoids. Multivariate analysis of the Raman hyperspectral imaging data revealed the presence of typical carotenoids and structurally similar but different polyenes, whose spatial distributions within the pink biofilm were found to be mutually exclusive. Raman measurements on individual microbial cells isolated from the pink biofilm confirmed that these distributions probed by carotenoid/polyene Raman signatures are attributable to different pigmented microorganisms. The present results suggest that Raman microspectroscopy with a focus on microbial pigments such as carotenoids is a powerful nondestructive method for studying multispecies biofilms in various environments.

Successfully interfacing enzymes and biomachinery with polymers affords on-demand modification and/or programmable degradation during the manufacture, utilization and disposal of plastics, but requires controlled biocatalysis in solid matrices with macromolecular substrates 1 – 7 . Embedding enzyme microparticles speeds up polyester degradation, but compromises host properties and unintentionally accelerates the formation of microplastics with partial polymer degradation 6 , 8 , 9 . Here we show that by nanoscopically dispersing enzymes with deep active sites, semi-crystalline polyesters can be degraded primarily via chain-end-mediated processive depolymerization with programmable latency and material integrity, akin to polyadenylation-induced messenger RNA decay 10 . It is also feasible to achieve processivity with enzymes that have surface-exposed active sites by engineering enzyme–protectant–polymer complexes. Poly(caprolactone) and poly(lactic acid) containing less than 2 weight per cent enzymes are depolymerized in days, with up to 98 per cent polymer-to-small-molecule conversion in standard soil composts and household tap water, completely eliminating current needs to separate and landfill their products in compost facilities. Furthermore, oxidases embedded in polyolefins retain their activities. However, hydrocarbon polymers do not closely associate with enzymes, as their polyester counterparts do, and the reactive radicals that are generated cannot chemically modify the macromolecular host. This study provides molecular guidance towards enzyme–polymer pairing and the selection of enzyme protectants to modulate substrate selectivity and optimize biocatalytic pathways. The results also highlight the need for in-depth research in solid-state enzymology, especially in multi-step enzymatic cascades, to tackle chemically dormant substrates without creating secondary environmental contamination and/or biosafety concerns. Nanoscopic dispersion of enzymes with deep active sites enables chain-end-mediated processive biodegradation of semi-crystalline polyesters with programmable latency and material integrity.

The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A₁ and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin’s shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin’s biosynthesis including a subcluster of genes consistent with selvamicin’s 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10–0.83 μg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 μg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC50 values ranging from 2.07 to 11.50 µM.

Lysobacter is known as a bacterial genus with biotechnological potential, producing an array of enzymes, antimicrobial metabolites, and bioactive antioxidant compounds, including aryl polyene (APE) pigments that have been described as protecting substances against photooxidative damage and lipid peroxidation. In this study, the pigment extracted from keratinolytic Lysobacter sp. A03 isolated from Antarctic environment was characterized. The results of KOH test, UV–vis spectroscopy, CIELAB color system, 1 H-NMR, and FTIR-ATR spectroscopy suggest the pigment is a yellow xanthomonadin-like pigment. The in vitro antioxidant activity of the pigment was confirmed by the scavenging of ABTS and DPPH radicals. In silico analysis of the genome through antiSMASH software was also performed and the secondary metabolite gene clusters for APE and resorcinol synthesis were identified, suggesting that proteins responsible for the pigment biosynthesis are encoded in Lysobacter A03 genome.

Strain HA10002 was isolated from mangrove sediment collected from Dongzhaigang Mangrove Reserve in Hainan, China. It was selected with potent nematicidal activity and was identified as Streptomyces albogriseolus . By bioassay-guided fractionation, a new active component A22-1(S1) against root-knot nematodes was separated from its fermentation broth. On the basis of spectroscopic analyses and comparison with the data from correlative literature, the structure of S1 was established to be 6′-methyl-fungichromin, named as fungichromin B in this paper. The LD50 values of fungichromin B to the 2-stage juveniles of Meloidogyne incognita and Meloidogyne javanica were 7.64 and 7.83 μg/ml, respectively. Further examination demonstrated fungichromin B still showed a wide antifungal spectrum, as with fungichromin.