Fungerps: discovery of the glucan synthase inhibitor enfumafungin and development of a new class of antifungal triterpene glycosides.

Covering: up to 2024Fungal pathogens are a major threat to public health, with emerging resistance to all three classes of antifungals that are currently available and increased incidence of invasive fungal infections among hospitalized patients. Ibrexafungerp is a semi-synthetic analog of enfumafungin and the first antifungal agent approved in more than 20 years since the launch of caspofungin, the first of echinocandins. This new drug approval was made possible after a long arduous journey lasting 25 years by dedicated and talented medicinal chemists from two companies that undertook tedious atom-by-atom chemical modification of the natural product enfumafungin, a glycosylated fernane-type triterpenoid isolated from the fungus .

Genome-Led Discovery of the Antibacterial Cyclic Lipopeptide Kutzneridine A and Its Silent Biosynthetic Gene Cluster from Species.

Genome analysis of sp. CA-103260 revealed a putative lipopeptide-encoding biosynthetic gene cluster (BGC) that was cloned into a bacterial artificial chromosome (BAC) and heterologously expressed in M1152. As a result, a novel cyclic lipo-tetrapeptide containing two diaminopropionic acid residues and an exotic ,-acetonide ring, kutzneridine A (), was isolated and structurally characterized.

Endocarditis in Adult Congenital Heart Disease Patients: Prevention, Recognition, and Management.

Purpose Of Review: Present an updated overview of the prevention, diagnosis, and management of infective endocarditis in adult patients with congenital heart disease.

Recent Findings: Care for patients with infective endocarditis is changing in the areas of specialized teams, diagnostics, and prevention. Endocarditis teams should be involved in the care of ACHD patients.

Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age.

Escuzarmycins A-D, Potent Biofungicides to Control Blotch.

A study targeting novel antifungal metabolites identified potent antifungal activity against key plant pathogens in acetone extracts of sp. strain CA-296093. Feature-based molecular networking revealed the presence in this extract of antimycin-related compounds, leading to the isolation of four new compounds: escuzarmycins A-D (-).

Cellulamides: A New Family of Marine-Sourced Linear Peptides from the Underexplored Genus.

Bioprospecting the secondary metabolism of underexplored Actinomycetota taxa is a prolific route to uncover novel chemistry. In this work, we report the isolation, structure elucidation, and bioactivity screening of cellulamides A and B ( and ), two novel linear peptides obtained from the culture of the macroalga-associated CT-R177. The host of this microorganism, the Chlorophyta , was collected in the northern Portuguese coast and, in the scope of a bioprospecting study focused on its associated actinobacterial community, strain CT-R177 was isolated, taxonomically identified, and screened for the production of antimicrobial and anticancer compounds.

Onychocolone A produced by the fungus Onychocola sp. targets cancer stem cells and stops pancreatic cancer progression by inhibiting MEK2-dependent cell signaling.

Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds.

Highly Concentrated Linear Guanidine Amides from the Marine Sipunculid .

The chemical diversity of annelids, particularly those belonging to the class Sipuncula, remains largely unexplored. However, as part of a Marine Biodiscovery program in Ireland, the peanut worm emerged as a promising source of unique metabolites. The purification of the MeOH/CHCl extract of this species led to the isolation of six new linear guanidine amides, named phascolosomines A-F (-).

Discovery of bioactive natural products of microbial origin as inhibitors of the PD-1/PD-L1 protein-protein interaction.

The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging.

Unearthing a Cryptic Biosynthetic Gene Cluster for the Piperazic Acid-Bearing Depsipeptide Diperamycin in the Ant-Dweller sp. CS113.

Piperazic acid is a cyclic nonproteinogenic amino acid that contains a hydrazine N-N bond formed by a piperazate synthase (KtzT-like). This amino acid, found in bioactive natural products synthesized by non-ribosomal peptide synthetases (NRPSs), confers conformational constraint to peptides, an important feature for their biological activities. Genome mining of strains has been revealed as a strategy to identify biosynthetic gene clusters (BGCs) for potentially active compounds.

Dilarmycins A-C, Calcium-Dependent Lipopeptide Antibiotics with a Non-canonical Ca-Binding Motif.

Genome analysis of strain sp. CA-278952 revealed a biosynthetic gene cluster encoding a putative lipopeptide with a sequence containing an Asp-Gly-Glu-Ala motif. We envisioned that this motif could mimic the canonical Asp-X-Asp-Gly sequence found in previously reported calcium-dependent lipopeptide antibiotics.

Uncovering the biotechnological capacity of marine and brackish water Planctomycetota.

An appealing strategy for finding novel bioactive molecules in Nature consists in exploring underrepresented and -studied microorganisms. Here, we investigated the antimicrobial and tumoral anti-proliferative bioactivities of twenty-three marine and estuarine bacteria of the fascinating phylum Planctomycetota. This was achieved through extraction of compounds produced by the Planctomycetota cultured in oligotrophic medium followed by an antimicrobial screening against ten relevant human pathogens including Gram-positive and Gram-negative bacteria, and fungi.

Naphthoquinone Derivatives from CF-097565 Display Anti-Tumour Activity in 3D Cultures of Breast Cancer Cells.

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus CF-097565.

Unveiling the bioactive potential of Actinomycetota from the Tagus River estuary.

The increase in global travel and the incorrect and excessive use of antibiotics has led to an unprecedented rise in antibiotic resistance in bacterial and fungal populations. To overcome these problems, novel bioactive natural products must be discovered, which may be found in underexplored environments, such as estuarine habitats. In the present work, estuarine actinomycetotal strains were isolated with conventional and iChip techniques from the Tagus estuary in Alcochete, Portugal, and analysed for different antimicrobial bioactivities.

Madurastatins with Imidazolidinone Rings: Natural Products or Side-Reaction Products from Extraction Solvents?

Madurastatins are a group of pentapeptides containing an oxazoline moiety, and, in a few cases, an imidazolidinone ring as an additional structural feature. In our search for new potential antiparasitic metabolites from natural sources, we studied the acetone extracts from a culture of sp. CA-135719.

Evaluation of pro-regenerative and anti-inflammatory effects of isolecanoric acid in the muscle: Potential treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating degenerative disease of skeletal muscles caused by loss of dystrophin, a key protein that maintains muscle integrity, which leads to progressive muscle degeneration aggravated by chronic inflammation, muscle stem cells' (MuSCs) reduced regenerative capacity and replacement of muscle with fibroadipose tissue. Previous research has shown that pharmacological GSK-3β inhibition favors myogenic differentiation and plays an important role in modulating inflammatory processes. Isolecanoric acid (ILA) is a natural product isolated from a fungal culture displaying GSK-3β inhibitory properties.

Additional Sarasinosides from the Marine Sponge Collected from the Bismarck Sea.

In our continuing efforts to describe the biological and chemical diversity of sponges from Kimbe Bay, Papua New Guinea, the known 30-norlanostane saponin sarasinoside C () was identified along with six new analogues named sarasinosides C, C, C, C, C, and C (-) from the sponge . The structures of the new compounds were elucidated by analysis of 1D and 2D NMR and HRMS data, as well as comparison with literature data. All new compounds are characterized by the same tetraose moiety, β-d-Xyl-(1→6)-β-d-GlcNAc-(1→2)-[β-d-GalNAc-(1→4)]-β-d-Xyl, as described previously for sarasinoside C, but differed in their aglycone moieties.

Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity.

The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production.

Xerophytic Lichens from Gypsiferous Outcrops of Arid Areas of Andalusia as a Source of Anti-Phytopathogenic Depsides.

In a survey to evaluate the potential of lichens associated with gypsum areas as sources of new antifungal metabolites, six species of lichens were collected in the gypsum outcrops of the Sorbas Desert ( and ) and the Tabernas Desert (, , and ) in southern Spain. Raw lichen acetone extracts were tested against a panel of seven phytopathogenic fungi, including , , f.sp TR4, , , and .

Strasseriolides display in vitro and in vivo activity against trypanosomal parasites and cause morphological and size defects in Trypanosoma cruzi.

Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates.

New Phocoenamicin and Maklamicin Analogues from Cultures of Three Marine-Derived Strains.

Antimicrobial resistance can be considered a hidden global pandemic and research must be reinforced for the discovery of new antibiotics. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, compounds displaying different antibiotic activities. Three marine strains (CA-214671, CA-214658 and CA-218877), identified as phocoenamicins producers, were chosen to scale up their production and LC/HRMS analyses proved that EtOAc extracts from their culture broths produce several structurally related compounds not disclosed before.

TC1 symbiont suppresses malaria transmission by anopheline mosquitoes.

Malaria control demands the development of a wide range of complementary strategies. We describe the properties of a naturally occurring, non-genetically modified symbiotic bacterium, TC1, which was isolated from mosquitoes incapable of sustaining the development of parasites. TC1 inhibits early stages of development and subsequent transmission by the mosquito through secretion of a small-molecule inhibitor.

sp. nov., isolated from marine beach sediment.

A novel actinomycetal strain, designated M600PL45_2, was isolated from marine sediments obtained from Ingleses beach, Porto, on the Northern Coast of Portugal and was subjected to a polyphasic taxonomic characterisation study. The here described Gram-reaction-positive strain is characterised by the production of a brown pigment in both solid and liquid medium and forms typical helical hyphae that differentiate into smooth spores. The results of a phylogenetic analysis based on the 16S rRNA gene sequence indicated that M600PL45_2 has a high similarity to two members of the genus , ASO4wet (98.