Antibiotic origami: selective formation of spirotetronates in abyssomicin biosynthesis.

The abyssomicins are a structurally intriguing family of bioactive natural products that include compounds with potent antibacterial, antitumour and antiviral activities. The biosynthesis of the characteristic abyssomicin spirotetronate core occurs via an enzyme-catalysed intramolecular Diels-Alder reaction, which proceeds via one of two distinct stereochemical pathways to generate products differing in configuration at the C15 spirocentre. Using the purified spirotetronate cyclases AbyU (from abyssomicin C/atrop-abyssomicin C biosynthesis) and AbmU (from abyssomicin 2/neoabyssomicin biosynthesis), in combination with synthetic substrate analogues, here we show that stereoselectivity in the spirotetronate-forming [4 + 2]-cycloaddition is controlled by a combination of factors attributable to both the enzyme and substrate. Furthermore, an achiral substrate was enzymatically cyclised to a single enantiomer of a spirocyclic product. X-ray crystal structures, molecular dynamics simulations, and assessment of substrate binding affinity and reactivity in both AbyU and AbmU establish the molecular determinants of stereochemical control in this important class of biocatalysts.

Molecular basis of hyper-thermostability in the thermophilic archaeal aldolase MfnB.

Methanogenic archaea are chemolithotrophic prokaryotes that can reduce carbon dioxide with hydrogen gas to form methane. These microorganisms make a significant contribution to the global carbon cycle, with methanogenic archaea from anoxic environments estimated to contribute > 500 million tons of global methane annually. Archaeal methanogenesis is dependent on the methanofurans; aminomethylfuran containing coenzymes that act as the primary C1 acceptor molecule during carbon dioxide fixation. Although the biosynthetic pathway to the methanofurans has been elucidated, structural adaptations which confer thermotolerance to Mfn enzymes from extremophilic archaea are yet to be investigated. Here we focus on the methanofuran biosynthetic enzyme MfnB, which catalyses the condensation of two molecules of glyceralde-3-phosphate to form 4­(hydroxymethyl)-2-furancarboxaldehyde-phosphate. In this study, MfnB enzymes from the hyperthermophile Methanocaldococcus jannaschii and the mesophile Methanococcus maripaludis have been recombinantly overexpressed and purified to homogeneity. Thermal unfolding studies, together with steady-state kinetic assays, demonstrate thermoadaptation in the M. jannaschii enzyme. Molecular dynamics simulations have been used to provide a structural explanation for the observed properties. These reveal a greater number of side chain interactions in the M. jannaschii enzyme, which may confer protection from heating effects by enforcing spatial residue constraints.

Delineation of the complete reaction cycle of a natural Diels-Alderase.

The Diels-Alder reaction is one of the most effective methods for the synthesis of substituted cyclohexenes. The development of protein catalysts for this reaction remains a major priority, affording new sustainable routes to high value target molecules. Whilst a small number of natural enzymes have been shown capable of catalysing [4 + 2] cycloadditions, there is a need for significant mechanistic understanding of how these prospective Diels-Alderases promote catalysis to underpin their development as biocatalysts for use in synthesis. Here we present a molecular description of the complete reaction cycle of the bona fide natural Diels-Alderase AbyU, which catalyses formation of the spirotetronate skeleton of the antibiotic abyssomicin C. This description is derived from X-ray crystallographic studies of AbyU in complex with a non-transformable synthetic substrate analogue, together with transient kinetic analyses of the AbyU catalysed reaction and computational reaction simulations. These studies reveal the mechanistic intricacies of this enzyme system and establish a foundation for the informed reengineering of AbyU and related biocatalysts.

Diversity and structure of the deep-sea sponge microbiome in the equatorial Atlantic Ocean.

Sponges (phylum Porifera) harbour specific microbial communities that drive the ecology and evolution of the host. Understanding the structure and dynamics of these communities is emerging as a primary focus in marine microbial ecology research. Much of the work to date has focused on sponges from warm and shallow coastal waters, while sponges from the deep ocean remain less well studied. Here, we present a metataxonomic analysis of the microbial consortia associated with 23 individual deep-sea sponges. We identify a high abundance of archaea relative to bacteria across these communities, with certain sponge microbiomes comprising more than 90 % archaea. Specifically, the archaeal family Nitrosopumilaceae is prolific, comprising over 99 % of all archaeal reads. Our analysis revealed that sponge microbial communities reflect the host sponge phylogeny, indicating a key role for host taxonomy in defining microbiome composition. Our work confirms the contribution of both evolutionary and environmental processes to the composition of microbial communities in deep-sea sponges.

Beak and feather disease virus detected in the endangered Red Goshawk (Erythrotriorchis radiatus).

We report the first detection and prevalence of Beak and feather disease virus (BFDV) in Australia's Red Goshawk (Erythrotriorchis radiatus). This is a new host for this pervasive pathogen amongst a growing list of non-psittacine species including birds of prey from the orders Accipitriformes (hawks, eagles, kites), Falconiformes (falcons and caracas), and Strigiformes (owls). The Red Goshawk is the first non-psittacine species listed as Endangered to be diagnosed with BFDV. We report an initial case of infection discovered post-mortem in a dead nestling and subsequent surveillance of birds from across northern Australia. We reveal BFDV prevalence rates in a wild raptor population for the first time, with detections in 25% (n = 7/28) of Red Goshawks sampled. Prevalence appears higher in juveniles compared to adults, although not statistically significant, but is consistent with studies of wild psittacines. BFDV genotypes were associated with the Loriinae (lorikeets, budgerigar, and fig parrots), Cacatuini (Cockatoos), and Polytelini (long-tailed parrots) tribes; species which are preyed upon by Red Goshawks. A positive BFDV status may be associated with lower body mass but small sample sizes precluded robust statistical analysis. We postulate the possible impacts of the virus on Red Goshawks and discuss future research priorities given these preliminary observations.

Assessing adequacy of citizen science datasets for biodiversity monitoring.

Tracking the state of biodiversity over time is critical to successful conservation, but conventional monitoring schemes tend to be insufficient to adequately quantify how species' abundances and distributions are changing. One solution to this issue is to leverage data generated by citizen scientists, who collect vast quantities of data at temporal and spatial scales that cannot be matched by most traditional monitoring methods. However, the quality of citizen science data can vary greatly. In this paper, we develop three metrics (inventory completeness, range completeness, spatial bias) to assess the adequacy of spatial observation data. We explore the adequacy of citizen science data at the species level for Australia's terrestrial native birds and then model these metrics against a suite of seven species traits (threat status, taxonomic uniqueness, body mass, average count, range size, species density, and human population density) to identify predictors of data adequacy. We find that citizen science data adequacy for Australian birds is increasing across two of our metrics (inventory completeness and range completeness), but not spatial bias, which has worsened over time. Relationships between the three metrics and seven traits we modelled were variable, with only two traits having consistently significant relationships across the three metrics. Our results suggest that although citizen science data adequacy has generally increased over time, there are still gaps in the spatial adequacy of citizen science for monitoring many Australian birds. Despite these gaps, citizen science can play an important role in biodiversity monitoring by providing valuable baseline data that may be supplemented by information collected through other methods. We believe the metrics presented here constitute an easily applied approach to assessing the utility of citizen science datasets for biodiversity analyses, allowing researchers to identify and prioritise regions or species with lower data adequacy that will benefit most from targeted monitoring efforts.

A horizon scan of global biological conservation issues for 2024.

We present the results of our 15th horizon scan of novel issues that could influence biological conservation in the future. From an initial list of 96 issues, our international panel of scientists and practitioners identified 15 that we consider important for societies worldwide to track and potentially respond to. Issues are novel within conservation or represent a substantial positive or negative step-change with global or regional extents. For example, new sources of hydrogen fuel and changes in deep-sea currents may have profound impacts on marine and terrestrial ecosystems. Technological advances that may be positive include benchtop DNA printers and the industrialisation of approaches that can create high-protein food from air, potentially reducing the pressure on land for food production.

Molecular mechanisms underpinning favourable physiological adaptations to exercise prehabilitation for urological cancer surgery.

BACKGROUND: Surgery for urological cancers is associated with high complication rates and survivors commonly experience fatigue, reduced physical ability and quality of life. High-intensity interval training (HIIT) as surgical prehabilitation has been proven effective for improving the cardiorespiratory fitness (CRF) of urological cancer patients, however the mechanistic basis of this favourable adaptation is undefined. Thus, we aimed to assess the mechanisms of physiological responses to HIIT as surgical prehabilitation for urological cancer. METHODS: Nineteen male patients scheduled for major urological surgery were randomised to complete 4-weeks HIIT prehabilitation (71.6 ± 0.75 years, BMI: 27.7 ± 0.9 kg·m2) or a no-intervention control (71.8 ± 1.1 years, BMI: 26.9 ± 1.3 kg·m2). Before and after the intervention period, patients underwent m. vastus lateralis biopsies to quantify the impact of HIIT on mitochondrial oxidative phosphorylation (OXPHOS) capacity, cumulative myofibrillar muscle protein synthesis (MPS) and anabolic, catabolic and insulin-related signalling. RESULTS: OXPHOS capacity increased with HIIT, with increased expression of electron transport chain protein complexes (C)-II (p = 0.010) and III (p = 0.045); and a significant correlation between changes in C-I (r = 0.80, p = 0.003), C-IV (r = 0.75, p = 0.008) and C-V (r = 0.61, p = 0.046) and changes in CRF. Neither MPS (1.81 ± 0.12 to 2.04 ± 0.14%·day-1, p = 0.39) nor anabolic or catabolic proteins were upregulated by HIIT (p > 0.05). There was, however, an increase in phosphorylation of AS160Thr642 (p = 0.046) post-HIIT. CONCLUSIONS: A HIIT surgical prehabilitation regime, which improved the CRF of urological cancer patients, enhanced capacity for skeletal muscle OXPHOS; offering potential mechanistic explanation for this favourable adaptation. HIIT did not stimulate MPS, synonymous with the observed lack of hypertrophy. Larger trials pairing patient-centred and clinical endpoints with mechanistic investigations are required to determine the broader impacts of HIIT prehabilitation in this cohort, and to inform on future optimisation (i.e., to increase muscle mass).

Diastereoselective Self-Assembly of Low-Symmetry Pdn L2n Nanocages through Coordination-Sphere Engineering.

Metal-organic cages (MOCs) are popular host architectures assembled from ligands and metal ions/nodes. Assembling structurally complex, low-symmetry MOCs with anisotropic cavities can be limited by the formation of statistical isomer libraries. We set out to investigate the use of primary coordination-sphere engineering (CSE) to bias isomer selectivity within homo- and heteroleptic Pdn L2n cages. Unexpected differences in selectivities between alternative donor groups led us to recognise the significant impact of the second coordination sphere on isomer stabilities. From this, molecular-level insight into the origins of selectivity between cis and trans diastereoisomers was gained, highlighting the importance of both host-guest and host-solvent interactions, in addition to ligand design. This detailed understanding allows precision engineering of low-symmetry MOC assemblies without wholesale redesign of the ligand framework, and fundamentally provides a theoretical scaffold for the development of stimuli-responsive, shape-shifting MOCs.

Discovery and biosynthetic assessment of 'Streptomyces ortus' sp. nov. isolated from a deep-sea sponge.

The deep sea is known to host novel bacteria with the potential to produce a diverse array of undiscovered natural products. Thus, understanding these bacteria is of broad interest in ecology and could also underpin applied drug discovery, specifically in the area of antimicrobials. Here, we isolate a new strain of Streptomyces from the tissue of the deep-sea sponge Polymastia corticata collected at a depth of 1869 m from the Gramberg Seamount in the Atlantic Ocean. This strain, which was given the initial designation A15ISP2-DRY2T, has a genome size of 9.29 Mb with a G+C content of 70.83 mol%. Phylogenomics determined that A15ISP2-DRY2T represents a novel species within the genus Streptomyces as part of the Streptomyces aurantiacus clade. The biosynthetic potential of A15ISP2-DRY2T was assessed relative to other members of the S. aurantiacus clade via comparative gene cluster family (GCF) analysis. This revealed a clear congruent relationship between phylogeny and GCF content. A15ISP2-DRY2T contains six unique GCFs absent elsewhere in the clade. Culture-based assays were used to demonstrate the antibacterial activity of A15ISP2-DRY2T against two drug-resistant human pathogens. Thus, we determine A15ISP2-DRY2T to be a novel bacterial species with considerable biosynthetic potential and propose the systematic name 'Streptomyces ortus' sp. nov.

Global governance for pandemic prevention and the wildlife trade.

Although ideas about preventive actions for pandemics have been advanced during the COVID-19 crisis, there has been little consideration for how they can be operationalised through governance structures within the context of the wildlife trade for human consumption. To date, pandemic governance has mostly focused on outbreak surveillance, containment, and response rather than on avoiding zoonotic spillovers in the first place. However, given the acceleration of globalisation, a paradigm shift towards prevention of zoonotic spillovers is warranted as containment of outbreaks becomes unfeasible. Here, we consider the current institutional landscape for pandemic prevention in light of ongoing negotiations of a so-called pandemic treaty and how prevention of zoonotic spillovers from the wildlife trade for human consumption could be incorporated. We argue that such an institutional arrangement should be explicit about zoonotic spillover prevention and focus on improving coordination across four policy domains, namely public health, biodiversity conservation, food security, and trade. We posit that this pandemic treaty should include four interacting goals in relation to prevention of zoonotic spillovers from the wildlife trade for human consumption: risk understanding, risk assessment, risk reduction, and enabling funding. Despite the need to keep political attention on addressing the current pandemic, society cannot afford to miss the opportunity of the current crisis to encourage institution building for preventing future pandemics.

Correction: Back et al. A New Micromonospora Strain with Antibiotic Activity Isolated from the Microbiome of a Mid-Atlantic Deep-Sea Sponge. Mar. Drugs 2021, 19, 105.

After publication of this article [...].

Global assessment of the biodiversity safeguards of development banks that finance infrastructure.

Infrastructure development is a major driver of biodiversity loss globally. With upward of US$2.5 trillion in annual investments in infrastructure, the financial sector indirectly drives this biodiversity loss. At the same time, biodiversity safeguards (project-level biodiversity impact mitigation requirements) of infrastructure financiers can help limit this damage. The coverage and harmonization of biodiversity safeguards are important factors in their effectiveness and therefore warrant scrutiny. It is equally important to examine the extent to which these safeguards align with best-practice principles for biodiversity impact mitigation outlined in international policies, such as that of the International Union for Conservation of Nature. We assessed the biodiversity safeguards of public development banks and development finance institutions for coverage, harmonization, and alignment with best practice. We used Institute of New Structural Economics and Agence Française de Développement's global database to identify development banks that invest in high-biodiversity-footprint infrastructure and have over US$500 million in assets. Of the 155 banks, 42% (n = 65) had biodiversity safeguards. Of the existing safeguards, 86% (56 of 65) were harmonized with International Finance Corporation (IFC) Performance Standard 6 (PS6). The IFC PS6 (and by extension the 56 safeguard policies harmonized with it) had high alignment with international best practice in biodiversity impact mitigation, whereas the remaining 8 exhibited partial alignment, incorporating few principles that clarify the conditions for effective biodiversity offsetting. Given their dual role in setting benchmarks and leveraging private finance, infrastructure financiers in development finance need to adopt best-practice biodiversity safeguards if the tide of global biodiversity loss is to be stemmed. The IFC PS6, if strengthened, can act as a useful template for other financier safeguards. The high degree of harmonization among safeguards is promising, pointing to a potential for diffusion of practices.

Evaluación mundial de las salvaguardas para la biodiversidad de los bancos del desarrollo que financian la infraestructura Resumen El desarrollo infraestructural es una de las causas principales de la pérdida mundial de biodiversidad. Con más de US$2.5 billones de inversión anual en la infraestructura, el sector financiero impulsa de forma indirecta esta pérdida. Al mismo tiempo, las salvaguardas para la biodiversidad (los requerimientos para la mitigación del impacto sobre la biodiversidad a nivel proyecto) de los financiadores de la infraestructura pueden ayudar a limitar este daño. La cobertura y armonización de estas salvaguardas son factores importantes en su efectividad y por lo tanto requieren de escrutinio. Es igual de importante examinar en qué medida se ajustan estas salvaguardas con los principios de mejores prácticas para mitigar el impacto sobre la biodiversidad esbozados en las políticas internacionales, como las de la UICN. Analizamos las salvaguardas para la biodiversidad de los bancos del desarrollo público y las instituciones de financiamiento para el desarrollo en cuanto a cobertura, armonización y ajuste con las mejores prácticas. Usamos las bases de datos mundiales del Institute of New Structural Economics y de la Agence Française de Développement para identificar los bancos del desarrollo que invierten en infraestructuras con una gran huella de biodiversidad y que tienen más de US$500 millones en activos. De los 155 bancos, el 42% % (n = 65) tenía salvaguardas para la biodiversidad. De éstas, el 86% (56 de 65) armonizaba con el Estándar de Desempeño 6 (PS6) de la Corporación Financiera Internacional (IFC). El PS6 de la IFC (y por extensión, las 56 salvaguardas que armonizan con él) tuvo un gran ajuste con las mejores prácticas internacionales para la mitigación del impacto sobre la biodiversidad, mientras que las ocho faltantes exhibieron un ajuste parcial, pues incorporaban pocos principios que clarificaban las condiciones de una compensación efectiva de biodiversidad. Ya que los financiadores de la infraestructura tienen un papel doble estableciendo referencias e impulsando el financiamiento privado, también necesitan adoptar las mejores prácticas para salvaguardar la biodiversidad si se desea detener la pérdida de biodiversidad mundial. El PS6 de la IFC, si se fortalece, puede fungir como una plantilla útil para los demás financiadores de las salvaguardas. La gran armonización entre las salvaguardas es prometedora y apunta hacia un potencial de difusión de las prácticas.

Exploring the risks and benefits of flexibility in biodiversity offset location in a case study of migratory shorebirds.

Biodiversity offsets aim to counterbalance the residual impacts of development on species and ecosystems. Guidance documents explicitly recommend that biodiversity offset actions be located close to the location of impact because of higher potential for similar ecological conditions, but allowing greater spatial flexibility has been proposed. We examined the circumstances under which offsets distant from the impact location could be more likely to achieve no net loss or provide better ecological outcomes than offsets close to the impact area. We applied a graphical model for migratory shorebirds in the East Asian-Australasian Flyway as a case study to explore the problems that arise when incorporating spatial flexibility into offset planning. Spatially flexible offsets may alleviate impacts more effectively than local offsets; however, the risks involved can be substantial. For our case study, there were inadequate data to make robust conclusions about the effectiveness and equivalence of distant habitat-based offsets for migratory shorebirds. Decisions around offset placement should be driven by the potential to achieve equivalent ecological outcomes; however, when considering more distant offsets, there is a need to evaluate the likely increased risks alongside the potential benefits. Although spatially flexible offsets have the potential to provide more cost-effective biodiversity outcomes and more cobenefits, our case study showed the difficulty of demonstrating these benefits in practice and the potential risks that need to be considered to ensure effective offset placement.

Estudio de los riesgos y beneficios de la flexibilidad en la ubicación de compensación de la biodiversidad en el estudio de caso de aves costeras migratorias Resumen Las compensaciones de la biodiversidad buscan contrabalancear el impacto residual que tiene el desarrollo sobre las especies y los ecosistemas. Los documentos guía recomiendan explícitamente que las acciones de estas compensaciones estén ubicadas cerca del lugar del impacto debido al potencial elevado de que haya condiciones ecológicas similares, aunque ya hay propuestas de una mayor flexibilidad espacial. Analizamos las circunstancias bajo las cuales las compensaciones alejadas del lugar de impacto tendrían mayor probabilidad de lograr pérdidas netas nulas o de proporcionar mejores resultados ecológicos que las compensaciones cercanas al área de impacto. Aplicamos un modelo gráfico para las aves costeras migratorias en el corredor aéreo asiático-australasiático del este como estudio de caso para estudiar los problemas que surgen cuando se incorpora la flexibilidad espacial a la planeación de las compensaciones. Las compensaciones espacialmente flexibles pueden mitigar los impactos más efectivamente que las compensaciones locales; sin embargo, los riesgos que esto involucra pueden ser considerables. En nuestro estudio de caso hubo datos insuficientes para concluir contundentemente sobre la efectividad y equivalencia de las compensaciones basadas en los hábitats distantes para las aves costeras migratorias. Las decisiones en torno a la ubicación de las compensaciones deberían estar impulsadas por el potencial para obtener resultados ecológicos equivalentes; sin embargo, al considerar compensaciones más alejadas, existe la necesidad de evaluar el incremento probable de riesgos junto a los beneficios potenciales. Aunque las compensaciones espacialmente flexibles tienen el potencial para proporcionar resultados más rentables y más beneficios colaterales, nuestro estudio de caso mostró la dificultad para demostrar estos beneficios en la práctica y los riesgos potenciales que necesitan considerarse para asegurar una ubicación efectiva de las compensaciones.

The Role of Cytochrome†P450 AbyV in the Final Stages of Abyssomicin†C Biosynthesis.

Abyssomicin C and its atropisomer are potent inhibitors of bacterial folate metabolism. They possess complex polycyclic structures, and their biosynthesis has been shown to involve several unusual enzymatic transformations. Using a combination of synthesis and in vitro assays we reveal that AbyV, a cytochrome P450 enzyme from the aby gene cluster, catalyses a key late-stage epoxidation required for the installation of the characteristic ether-bridged core of abyssomicin C. The X-ray crystal structure of AbyV has been determined, which in combination with molecular dynamics simulations provides a structural framework for our functional data. This work demonstrates the power of combining selective carbon-13 labelling with NMR spectroscopy as a sensitive tool to interrogate enzyme-catalysed reactions in vitro with no need for purification.