From the CH 2 Cl 2 extract of the Antarctic sponge Dendrilla antarctica we found spongian diterpenes, including previously reported aplysulphurin (1), tetrahydroaplysulphurin-1 (2), membranolide (3), and darwinolide (4), utilizing a CH 2 Cl 2 / MeOH extraction scheme. However, the extracts also yielded diterpenes bearing one or more methyl acetal functionalities (5−9), two of which are previously unreported, while others are revised here. Further investigation of diterpene reactivity led to additional new metabolites (10−12), which identified them as well as the methyl acetals as artifacts from methanolysis of aplysulphurin. The bioactivity of the methanolysis products, membranoids A−H (5−12), as well as natural products 1−4, were assessed for activity against Leishmania donovani-infected J774A.1 macrophages, revealing insights into their structure/activity relationships. Four diterpenes, tetrahydroaplysulphurin-1 (2) as well as membranoids B (6), D (8), and G (11), displayed low micromolar activity against L. donovani with no discernible cytotoxicity against uninfected J774A.1 cells. Leishmaniasis is a neglected tropical disease that affects one million people every year and can be fatal if left untreated.
SummaryPrenylation is the addition of prenyl groups to peptide chains or metabolites via the condensation of geranyl-or isopentenyl-diphosphate moieties by geranyltranstransferases. Although this process is extensively studied in eukaryotes, little is known about the influence of prenylation in prokaryotic species. To explore the role of this modification in bacteria, we generated a mutation in the geranyltranstransferase (IspA) of Staphylococcus aureus. Quite strikingly, the ispA mutant completely lacked pigment and exhibited a previously undescribed small colony variant-like phenotype. Further pleiotropic defects in cellular behavior were noted, including impaired growth, decreased ATP production, increased sensitivity to oxidative stress, increased resistance to aminoglycosides and cationic antimicrobial peptides, and decreased resistance to cell wall-targeting antibiotics. These latter effects appear to result from differences in envelope composition as ispA mutants have highly diffuse cell walls (particularly at the septum), marked alterations in fatty acid composition and increased membrane fluidity. Taken together, these data present an important characterization of prokaryotic prenylation and demonstrate that this process is central to a wealth of pathways involved in mediating cellular homeostasis in S. aureus.
The subtidal red alga Plocamium cartilagineum was collected from the Western Antarctic Peninsula during the 2011 and 2017 austral summers. Bulk collections from specific sites corresponded to chemogroups identified by Young et al. in 2013. One of the chemogroups yielded several known acyclic halogenated monoterpenes (2–5) as well as undescribed compounds of the same class, anverenes B–D (6–8). Examination of another chemogroup yielded an undescribed cyclic halogenated monoterpene anverene E (9) as its major secondary metabolite. Elucidation of structures was achieved through one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) spectroscopy and negative chemical ionization mass spectrometry. Compounds 1–9 show moderate cytotoxicity against cervical cancer (HeLa) cells.
The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B–D (10–12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13–15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.
Polar marine biota have adapted to thrive under one of the ocean’s most inhospitable scenarios, where extremes of temperature, light photoperiod and ice disturbance, along with ecological interactions, have selected species with a unique suite of secondary metabolites. Organisms of Arctic and Antarctic oceans are prolific sources of natural products, exhibiting wide structural diversity and remarkable bioactivities for human applications. Chemical skeletons belonging to terpene families are the most commonly found compounds, whereas cytotoxic antimicrobial properties, the capacity to prevent infections, are the most widely reported activities from these environments. This review firstly summarizes the regulations on access and benefit sharing requirements for research in polar environments. Then it provides an overview of the natural product arsenal from Antarctic and Arctic marine organisms that displays promising uses for fighting human disease. Microbes, such as bacteria and fungi, and macroorganisms, such as sponges, macroalgae, ascidians, corals, bryozoans, echinoderms and mollusks, are the main focus of this review. The biological origin, the structure of terpenes and terpenoids, derivatives and their biotechnological potential are described. This survey aims to highlight the chemical diversity of marine polar life and the versatility of this group of biomolecules, in an effort to encourage further research in drug discovery.
Synopsis Dense macroalgal forests on the Western Antarctic Peninsula serve important ecological roles both in terms of considerable biomass for primary production as well as in being ecosystem engineers. Their function within the Antarctic ecosystem has been described as a crucial member of a community-wide mutualism which benefits macroalgal species and dense assemblages of associated amphipod grazers. However, there is a cheater within the system that can feed on one of the most highly chemically defended macroalgal hosts. The amphipod Paradexamine fissicauda has been found to readily consume the finely branched red macroalga Plocamium cartilagineum. This amphipod grazer not only feeds on its host, but also appears to sequester its host’s chemical defenses for its own utilization. This review summarizes what we know about both of these exceptions to the community-wide mutualism.
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