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Natural product generation and diversification through blending synthetic biology and synthetic chemistry
No full textAntimicrobial resistance is a modern threat to our society, with more than 33000 cases of deaths reported in Europe in 2015 relating to human infection by antibiotic resistant bacteria. Since 1981, 70% of approved antibacterial agents have been obtained, derived, or inspired from natural products. The generation of natural product analogues can be very challenging, but can lead to improved bioactivity, bioavailability, and also help understanding the mechanism and interaction between the natural product antibiotic and the bacterial target.
By blending synthetic chemistry with synthetic biology, we can use the best of both worlds and access more efficiently the desired analogues. Synthetic biology approaches can be used to engineer a chemically reactive and orthogonal handle such as an epoxide or halogen into a molecule, providing a site for selective synthetic diversification. Using synthesis, precursor-directed biosynthesis and GenoChemetics, a new approach pioneered by the Goss group, I worked toward accessing analogues of 4 natural products.
Chapter 2 describes GenoChemetic studies on biosynthetic generation of new-to-nature brominated violacein analogues using a precursor-directed biosynthesis approach. This was achieved by heterologous expression of violacein biosynthetic gene cluster in E. coli; then feeding these cultures with brominated tryptophan analogues, leading to the production of 3 new brominated violacein analogues. Although all efforts for purification of the complex mixtures could not afford any pure bromo-violacein for NMR characterisation, a detailed LC-MS and MS-MS analysis allowed confirmation of the identity of these new natural products.
The mixture was used in chapter 3 to generate a further 29 analogues via Suzuki- Miyaura cross-coupling reactions. These products could be characterised by LC- MS. To complement the work presented, a total synthesis of one of the brominated analogues was achieved, NMR and LC-MS characterised, to compare with the biosynthetically generated bromo-violaceins. The synthetic material was used to generate 4 of the previously mentioned cross-coupling analogues and characterised to confirm the assignments made in chapter 3. These methods can be useful to generate libraries of violacein analogues using this GenoChemetic approach.
Chapter 4 details identification of cyclo-(Phe-Pro) diketopiperazine (DKP) natural product (isolated from microbial cultures in our labs) and chemical synthesis of various diastereomers to elucidate the stereochemistry of this natural product. Cyclo-(Phe-Pro) was investigated via a fully synthetic approach to generate analogues, comparing these analogues with naturally obtained samples. All 4 stereoisomers were generated, and 2 brominated analogues were also synthesised and characterised to test the robustness of the method. The antibiotic bioassays carried out were inconclusive. Relative stability and interconversion of diastereoisomers were also studied. This study provides a foundation for synthetic access to derivatives of DKP natural products.
In chapter 5, other natural non-ribosomal peptides, telomycin and kutznerides, were selected for analogue generation. Precursor-directed biosynthesis was employed to generate brominated analogues of both natural products."This work was supported by the EPSRC CRITICAT EP/L016419/1 for studentship support and also grateful to ERC GenoChemetics (FP7/2007-2013/ERC consolidator grant GCGXC grant agreement no 614779 RJMG) for funding."--Fundin
Lessons from enriching Tanzania’s clinical research ethics clinical trials oversight and pharmacovigilance through the ASCEND project
Get PDFFunding: This study was funded by the EDCTP through grant number CSA2019ERC-2683.Engaging in clinical trials in Africa not only enhances researchers' comprehension of local health concerns but also plays a crucial role in tackling global health challenges. In Tanzania, there has been a surge of clinical research for the past 10 years indicating a need to improve ethical and clinical trial regulatory capacity. Several initiatives to address the clinical trial regulatory and ethics challenges have been done. Lessons from such initiatives are important to inform evidence-based decision-making for sustainability. The ASCEND project with the theme of “Moving Tanzania’s Clinical Research Ethics and Medicines Regulatory Capacity to the Next Level: Fostering Medicine Quality, Safety and Good Clinical Practice (GCP) on Clinical Trials” was implemented in Tanzania Mainland and Zanzibar from November 2020 to December 2023. A thorough review of the project implementation reports and on deliverables was conducted to identify the lessons learned. Inductive content analysis was used to analyze the information. A total of seven lessons were deduced from the reviewed documents. These include capacity building through training on clinical trials review and approval process, research ethics and GCP inspection which cannot be overlooked; engaging the community in reporting adverse drug events is worth considering; digitalization of electronic systems enhances clinical trial control and creates a dynamic regulatory ecosystem; compliance to requirements for clinical trials conduct is enhanced by training of early and mid-career researchers; networking and broad stakeholders’ engagement and participation in ethics and regulations governing clinical trials is a cornerstone for strengthening collaboration between researchers and regulators; the need for electronic systems for monitoring and evaluation of the project is inevitable and the need for adhering to project timelines is crucial for successful implementation of the project. Sustainability is the take-home message from the ASCEND project and should inform stakeholders for future improvement. Continuous investment and advancement in research ethics and regulatory oversight across Africa should be prioritized.Peer reviewe
Evaluating the biosignature potential of ammonium in Proterozoic red beds and implications for the search for life on Mars
Get PDFFunding: EES acknowledges funding from a NERC Frontiers grant (NE/V010824/1) and from a Leverhulme Trust research grant (RPG-2022-313).Over the past two decades, it has become increasingly apparent that early Mars may once have been warmer, wetter and more habitable for microbial life than it is today, which has spurred discussions about potential biosignatures that may be preserved in Martian sediments. An impediment to this line of research is the pervasive oxidation of Mars’ surface due to photochemical oxidants that have likely destroyed remnants of organic matter. Here, we investigate whether nitrogen (N) transferred from biomass to phyllosilicate minerals during diagenesis can be preserved in oxidized mudrocks. We investigate two sequences of terrestrial Proterozoic red beds, namely the Sibley Group (1.4 Ga) in Canada and the Stoer Group (1.2 Ga) in Scotland, and we find enrichments in authigenic N in the range of several tens of ppm in both units. The highest concentrations (ca. 100 ppm on average) are found in the most desiccated red beds of the Stoer Group, concurrent with enrichments in potassium (K). We discuss similarities and differences between the two sets of rocks with regards to salinity, pH, biological productivity and K-metasomatism, and we conclude that the ideal mechanism for the preservation of biogenic N in red beds may be in-situ release of ammonium from microbial mats into the clay substrate, possibly facilitated by early diagenetic, biologically induced illitization. Illite and smectite have been observed on Mars, and experiments suggest that Martian waters contained moderate amounts of dissolved K. Hence, it is conceivable that a similar K and N enrichment process could have occurred as to what we document for the Proterozoic, preserving evidence of life that may have survived to the modern day.Peer reviewe
Plotting: a case study in lifted planning with constraints
Get PDFFunding: Ian Miguel is funded by EPSRC grant EP/V027182/1, Mateu Villaret is funded by MCIN/AEI/10.13039/501100011033 grant PID2021-122274OB-I00 and Peter Nightingale is funded by EPSRC grant EP/W001977/1.We study a planning problem based on Plotting, a tile-matching puzzle video game published by Taito in 1989. The objective of this turn-based game is to remove a target number of coloured blocks from a grid by sequentially shooting blocks into the same grid. Plotting features complex transitions after every shot: various blocks are affected directly, while others can be indirectly affected by gravity. We consider modelling and solving Plotting from two perspectives. The puzzle is naturally cast as an AI Planning problem and we first discuss modelling the problem using the Planning Domain Definition Language (PDDL). We find that a model in which planning actions correspond to player actions is inefficient with a grounding-based state-of-the-art planner. However, with a more fine-grained action model, where each change of a block is a planning action, solving performance is dramatically improved. We also describe two lifted constraint models, able to capture the inherent complexities of Plotting and enabling the application of efficient solving approaches from SAT and CP. Our empirical results with these models demonstrates that they can compete with, and often exceed, the performance of the dedicated planning solvers, suggesting that the richer languages available to constraint modelling can be of benefit when considering planning problems with complex changes of state. CP and SAT solvers solved almost all of the largest and most challenging instances within 1 hour, whereas the best planning approach solved approximately 30%. Finally, the flexibility provided by the constraint models allows us to easily curate interesting levels for human players.Peer reviewe
Using global remote camera data of a solitary species complex to evaluate the drivers of group formation
Get PDFThe social system of animals involves a complex interplay between physiology, natural history, and the environment. Long relied upon discrete categorizations of "social" and "solitary" inhibit our capacity to understand species and their interactions with the world around them. Here, we use a globally distributed camera trapping dataset to test the drivers of aggregating into groups in a species complex (martens and relatives, family , Order ) assumed to be obligately solitary. We use a simple quantification, the probability of being detected in a group, that was applied across our globally derived camera trap dataset. Using a series of binomial generalized mixed-effects models applied to a dataset of 16,483 independent detections across 17 countries on four continents we test explicit hypotheses about potential drivers of group formation. We observe a wide range of probabilities of being detected in groups within the solitary model system, with the probability of aggregating in groups varying by more than an order of magnitude. We demonstrate that a species' context-dependent proclivity toward aggregating in groups is underpinned by a range of resource-related factors, primarily the distribution of resources, with increasing patchiness of resources facilitating group formation, as well as interactions between environmental conditions (resource constancy/winter severity) and physiology (energy storage capabilities). The wide variation in propensities to aggregate with conspecifics observed here highlights how continued failure to recognize complexities in the social behaviors of apparently solitary species limits our understanding not only of the individual species but also the causes and consequences of group formation.Peer reviewe
Touching parchment : how medieval users rubbed, handled, and kissed their manuscripts - Volume 2: social encounters with the book
No full textFunding: This book has been partially funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy in the context of the Cluster of Excellence Temporal Communities: Doing Literature in a Global Perspective (EXC 2020–Project ID 390608380)
Testing the genomic overlap between intraspecific mating traits and interspecific mating barriers
Get PDFFunding: BBSRC (grant number BB/S019669/1) and NERC (grant numbers NE/I027800/1, NE/L011255/1, NE/T014806/1 and NE/W001616/1).Differences in interspecific mating traits, such as male sexual signals and female preferences, often evolve quickly as initial barriers to gene flow between nascent lineages, and they may also strengthen such barriers during secondary contact via reinforcement. However, it is an open question whether loci contributing to intraspecific variation in sexual traits are co-opted during the formation and strengthening of mating barriers between species. To test this, we used a population genomics approach in natural populations of Australian cricket sister species that overlap in a contact zone: Teleogryllus oceanicus and Teleogryllus commodus. First, we identified loci associated with intraspecific variation in T. oceanicus mating signals: advertisement song and cuticular hydrocarbon (CHC) pheromones. We then separately identified candidate interspecific barrier loci between the species. Genes showing elevated allelic divergence between species were enriched for neurological functions, indicating potential behavioral rewiring. Only two CHC-associated genes overlapped with these interspecific candidate barrier loci, and intraspecific CHC loci showed signatures of being under strong selective constraints between species. In contrast, 10 intraspecific song-associated genes showed high genetic differentiation between T. commodus and T. oceanicus, and 2 had signals of high genomic divergence. The overall lack of shared loci in intra vs. interspecific comparisons of mating trait and candidate barrier loci is consistent with limited co-option of the genetic architecture of interspecific mating signals during the establishment and maintenance of reproductive isolation.Peer reviewe
Towards specification-guarded refactoring
Get PDFFunding: This work was generously supported by UK EPSRC, EP/V006290.Refactoring is a common task in writing and maintaining software. Refactoring tools are available for a wide variety of programming languages, and they are intended to transform source code without altering the functional behaviour of the software being refactored. However, even though most refactoring tools are designed with this criterion in mind, and programmers expect it, their implementations do not provide formal guarantees of correctness. To address this limitation, we propose a methodology for extending refactoring implementations with correctness guarantees. Our approach leverages dependently-typed languages and techniques to guard refactoring implementations with proofs of conformance to formal specifications. We illustrate our proposed methodology using a renaming refactoring that includes correctness guarantees as an integral part of its implementation
4-Fluorobenzyl (Z)-2-(2-oxoindolin-3-ylidene) hydrazine-1-carbodithioate
Get PDFFunding: The authors acknowledge Universiti Teknologi MARA for financial support.The title compound, C16H12FN3OS, a fluorinated dithiocarbazate imine derivative, was synthesized by the one-pot, multi-component condensation reaction of hydrazine hydrate, carbon disulfide, 4-fluorobenzyl chloride and isatin. The compound demonstrates near-planarity across much of the molecule in the solid state and a Z configuration for the azomethine C N bond. The Z form is further stabilized by the presence of an intramolecular N—H. . .O hydrogen bond. In the extended structure, molecules are linked into dimers by N—H. . .O hydrogen bonds and further connected into chains along either [210] or [100] by weak C—H. . .S and C—H. . .F hydrogen bonds, which further link into corrugated sheets and in combination form the overall three-dimensional network.Peer reviewe
The JWST/NIRISS deep spectroscopic survey for young brown dwarfs and free-floating planets
Get PDFFunding: A.S. acknowledges support from the UKRI Science and Technology Facilities Council through grant ST/Y001419/1/. K.M. acknowledges support from the Fundação para a Ciência e a Tecnologia (FCT) through the CEEC-individual contract 2022.03809.CEECIND and research grants UIDB/04434/ 2020 and UIDP/04434/2020. R.J. acknowledges support from a Rockefeller Foundation Bellagio Residency. M.D.F. is supported by an NSF Astronomy and Astrophysics Postdoctoral Fellowship under award AST-2303911. D.J. is supported by NRC Canada and by an NSERC Discovery Grant.The discovery and characterization of free-floating planetary-mass objects (FFPMOs) is fundamental to our understanding of star and planet formation. Here we report results from an extremely deep spectroscopic survey of the young star cluster NGC1333 using Near-InfraRed Imager and Slitless Spectrograph (NIRISS) wide field slitless spectroscopy on the James Webb Space Telescope. The survey is photometrically complete to K ∼ 21, and includes useful spectra for objects as faint as K ∼ 20.5. The observations cover 19 known brown dwarfs, for most of which we confirm spectral types using NIRISS spectra. We discover six new candidates with L-dwarf spectral types that are plausible planetary-mass members of NGC1333, with estimated masses between 5 and 15 M Jup. One, at ∼5 M Jup, shows clear infrared excess emission and is a good candidate to be the lowest-mass object known to have a disk. We do not find any objects later than mid-L spectral type (M ≲ 4 M Jup). The paucity of Jupiter-mass objects, despite the survey’s unprecedented sensitivity, suggests that our observations reach the lowest-mass objects that formed like stars in NGC1333. Our findings put the fraction of FFPMOs in NGC1333 at ∼10% of the number of cluster members, significantly more than expected from the typical log-normal stellar mass function. We also search for wide binaries in our images and report a young brown dwarf with a planetary-mass companion.Peer reviewe
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