Pyrrolidine nucleoside bisphosphonates as antituberculosis agents targeting hypoxanthine-guanine phosphoribosyltransferase

Therapeutic treatment of tuberculosis (TB) is becoming increasingly problematic due to the emergence of drug resistant Mycobacterium tuberculosis (Mt). Thus, new targets for anti-TB drug discovery need to be identified to combat and eradicate this disease. One such target is hypoxanthine-guanine phosphoribosyltransferase (HGPRT) which synthesises the 6-oxopurine nucleoside monophosphates essential for DNA/RNA production. [3R,4R]-4-Hypoxanthin-9-yl-3-( (S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine and [3R,4R-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine (compound 6) are the most potent inhibitors of MtHGPRT yet discovered having K-i values of 60 nM. The crystal structure of the MtHGPRT.6 complex was obtained and compared with that of human HGPRT in complex with the same inhibitor. These structures provide explanations for the 60-fold difference in the inhibition constants between these two enzymes and a foundation for the design of next generation inhibitors. In addition, crystal structures of MtHGPRT in complex with two pyrrolidine nucleoside phosphosphonate inhibitors plus pyrophosphate provide insights into the final stage of the catalytic reaction. As the first step in ascertaining if such compounds have the potential to be developed as anti-TB therapeutics, the tetra-(ethyl L-phenylalanine) tetraamide prodrug of 6 was tested in cell based assays. This compound arrested the growth of virulent Mt not only in its replicating phase (IC50 of 14 mu M) but also in its latent phase (IC50 of 29 mu M). Furthermore, it arrested the growth of Mt in infected macrophages (MIC50 of 85 mu M) and has a low cytotoxicity in mammalian cells (CC50 of 132 +/- 20 mu M). These inhibitors are therefore viewed as forerunners of new anti-TB chemotherapeutics. (C) 2018 Elsevier Masson SAS. All rights reserved

Drawing lines at the sand: evidence for functional vs. visual reef boundaries in temperate Marine Protected Areas.

Marine Protected Areas (MPAs) can either protect all seabed habitats within them or discrete features. If discrete features within the MPA are to be protected humans have to know where the boundaries are. In Lyme Bay, SW England a MPA excluded towed demersal fishing gear from 206 km(2) to protect rocky reef habitats and the associated species. The site comprised a mosaic of sedimentary and reef habitats and so 'non reef' habitat also benefited from the MPA. Following 3 years protection, video data showed that sessile Reef Associated Species (RAS) had colonised sedimentary habitat indicating that 'reef' was present. This suggested that the functional extent of the reef was potentially greater than its visual boundary. Feature based MPA management may not adequately protect targeted features, whereas site based management allows for shifting baselines and will be more effective at delivering ecosystem goods and services

Australia's coastal fisheries and farmed seafood: an ecological basis for determining sustainability

In response to consumer concerns about the sustainability of Australian-sourced seafood we derive a set of criteria within an explicit decision-process that can be used to determine whether locally farmed and wild-caught Australian seafood products meet standards of ecological sustainability and Ecologically Sustainable Development. These criteria substantially address the ecological deficiencies we identified in other systems commonly used for assessing seafood sustainability. The criteria address the issues that are relevant to local seafood production, and are populated with indicators (metrics) and benchmarks relevant to the Australian context. The indicators establish performance thresholds drawn from public domain data about the products, including observed empirical data and proxies, and include default decisions to be applied in the absence of adequate information. This decision structure is set within a peer-reviewed expert jury decision-making process. The criteria, decision process and decision outcomes from assessment of a number of pilot products were tested in a real seafood market (Melbourne), where we found a high level of producer, reseller and consumer acceptance of the judgements and ratings. The use of ecologically-derived standards results in several outcomes that differ from those of other seafood assessment systems, especially those assessments more focused on production standards, such as government, industry and NGO-supported programs, popularly used in Australia and worldwide. We conclude that despite high levels of uncertainty surrounding many of the population parameters, ecological patterns and processes, empirical cost-effective proxies can be used to reasonably estimate a form of sustainability that matches consumer interests/expectations for production of fresh local seafood. Despite the plethora of industry and government programs, there remains a significant but presently unmet consumer demand for ecologically-based, technically robust, independently derived, and readily available information about the local sustainability attributes of Australian wild-caught and farmed fresh seafood

Effects of dredging on critical ecological processes for marine invertebrates, seagrasses and macroalgae, and the potential for management with environmental windows using Western Australia as a case study

Dredging can have significant impacts on benthic marine organisms through mechanisms such as sedimentation and reduction in light availability as a result of increased suspension of sediments. Phototrophic marine organisms and those with limited mobility are particularly at risk from the effects of dredging. The potential impacts of dredging on benthic species depend on biological processes including feeding mechanism, mobility, life history characteristics (LHCs), stage of development and environmental conditions. Environmental windows (EWs) are a management technique in which dredging activities are permitted during specific periods throughout the year; avoiding periods of increased vulnerability for particular organisms in specific locations. In this review we identify these critical ecological processes for temperate and tropical marine benthic organisms; and examine if EWs could be used to mitigate dredging impacts using Western Australia (WA) as a case study. We examined LHCs for a range of marine taxa and identified, where possible, their vulnerability to dredging. Large gaps in knowledge exist for the timing of LHCs for major species of marine invertebrates, seagrasses and macroalgae, increasing uncertainty around their vulnerability to an increase in suspended sediments or light attenuation. We conclude that there is currently insufficient scientific basis to justify the adoption of generic EWs for dredging operations in WA for any group of organisms other than corals and possibly for temperate seagrasses. This is due to; 1) the temporal and spatial variation in the timing of known critical life history stages of different species; and 2) our current level of knowledge and understanding of the critical life history stages and characteristics for most taxa and for most areas being largely inadequate to justify any meaningful EW selection. As such, we suggest that EWs are only considered on a case-by-case basis to protect ecologically or economically important species for which sufficient location-specific information is available, with consideration of probable exposures associated with a given mode of dredging