DSpace Collection:https://hdl.handle.net/2440/162024-03-29T14:43:21Z2024-03-29T14:43:21ZRepurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activityMackie, E.R.R.Barrow, A.S.Giel, M.-C.Hulett, M.D.Gendall, A.R.Panjikar, S.Soares da Costa, T.P.https://hdl.handle.net/2440/1403002024-01-08T06:38:46Z2023-01-01T00:00:00ZTitle: Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity
Author: Mackie, E.R.R.; Barrow, A.S.; Giel, M.-C.; Hulett, M.D.; Gendall, A.R.; Panjikar, S.; Soares da Costa, T.P.
Abstract: Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicide-resistant weeds. Here, we employed a novel strategy to repurpose a 'failed' antibiotic into a new and target-specific herbicidal compound. Specifically, we identified an inhibitor of bacterial dihydrodipicolinate reductase (DHDPR), an enzyme involved in lysine biosynthesis in plants and bacteria, that exhibited no antibacterial activity but severely attenuated germination of the plant Arabidopsis thaliana. We confirmed that the inhibitor targets plant DHDPR orthologues in vitro, and exhibits no toxic effects against human cell lines. A series of analogues were then synthesised with improved efficacy in germination assays and against soil-grown A. thaliana. We also showed that our lead compound is the first lysine biosynthesis inhibitor with activity against both monocotyledonous and dicotyledonous weed species, by demonstrating its effectiveness at reducing the germination and growth of Lolium rigidum (rigid ryegrass) and Raphanus raphanistrum (wild radish). These results provide proof-of-concept that DHDPR inhibition may represent a much-needed new herbicide mode of action. Furthermore, this study exemplifies the untapped potential of repurposing 'failed' antibiotic scaffolds to fast-track the development of herbicide candidates targeting the respective plant enzymes.2023-01-01T00:00:00ZA feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growthGillis, J.L.Hinneh, J.A.Ryan, N.K.Irani, S.Moldovan, M.Quek, L.-E.Shrestha, R.Hanson, A.R.Xie, J.Hoy, A.J.Holst, J.Centenera, M.M.Mills, I.G.Lynn, D.J.Selth, L.A.Butler, L.M.https://hdl.handle.net/2440/1402842023-12-21T03:01:14Z2021-01-01T00:00:00ZTitle: A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
Author: Gillis, J.L.; Hinneh, J.A.; Ryan, N.K.; Irani, S.; Moldovan, M.; Quek, L.-E.; Shrestha, R.; Hanson, A.R.; Xie, J.; Hoy, A.J.; Holst, J.; Centenera, M.M.; Mills, I.G.; Lynn, D.J.; Selth, L.A.; Butler, L.M.
Abstract: Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.
Description: Published: 12 August 20212021-01-01T00:00:00ZCell Wall Responses to Biotrophic Fungal Pathogen InvasionChowdhury, J.Coad, B.Little, A.https://hdl.handle.net/2440/1402152023-12-18T03:51:24Z2019-01-01T00:00:00ZTitle: Cell Wall Responses to Biotrophic Fungal Pathogen Invasion
Author: Chowdhury, J.; Coad, B.; Little, A.
Abstract: To a plant the surrounding environment is filled with microbial organisms looking to take advantage of the bountiful resources held within. In order for a pathogen to access the internal nutrients it must gain entry through the plant cell outer layers that consist of the cuticular wax and the plant cell wall. This barrier is a complex structure composed of diverse waxes, lipids, polysaccharides, proteins, lignin, and antimicrobial compounds and plays many crucial roles during plant defence, growth, and development. We now have more evidence than ever about the dynamic nature of the cell wall providing various interaction-dependent passive and active defence responses, hence justifying a necessity of evolving such a complex structure. Here we summarise the current understanding of this multi-layered defence system, using the biotrophic interaction between barley and the causal agent of powdery mildew, Blumeria graminis f. sp. hordei (Bgh).
Description: First published: 15 November 20192019-01-01T00:00:00ZSpectral reflectance indices as proxies for yield potential and heat stress tolerance in spring wheat: Heritability estimates and marker-trait associationsLiu, C.Pinto, F.Cossani, C.M.Sukumaran, S.Reynolds, M.P.https://hdl.handle.net/2440/1401672023-12-15T06:33:25Z2019-01-01T00:00:00ZTitle: Spectral reflectance indices as proxies for yield potential and heat stress tolerance in spring wheat: Heritability estimates and marker-trait associations
Author: Liu, C.; Pinto, F.; Cossani, C.M.; Sukumaran, S.; Reynolds, M.P.
Abstract: The application of spectral reflectance indices (SRIs) as proxies to screen for yield potential (YP) and heat stress (HS) is emerging in crop breeding programs. Thus, a comparison of SRIs and their associations with grain yield (GY) under YP and HS conditions is important. In this study, we assessed the usefulness of 27 SRIs for indirect selection for agronomic traits by evaluating an elite spring wheat association mapping initiative (WAMI) population comprising 287 elite lines under YP and HS conditions. Genetic and phenotypic analysis identified 11 and 9 SRIs in different developmental stages as efficient indirect selection indices for yield in YP and HS conditions, respectively. We identified enhanced vegetation index (EVI) as the common SRI associated with GY under YP at booting, heading and late heading stages, whereas photochemical reflectance index (PRI) and normalized difference vegetation index (NDVI) were the common SRIs under booting and heading stages in HS. Genomewide association study (GWAS) using 18704 single nucleotide polymorphisms (SNPs) from Illumina iSelect 90K identified 280 and 43 marker-trait associations for efficient SRIs at different developmental stages under YP and HS, respectively. Common genomic regions for multiple SRIs were identified in 14 regions in 9 chromosomes: 1B (60–62 cM), 3A (15, 85–90, 101– 105 cM), 3B (132–134 cM), 4A (47–51 cM), 4B (71– 75 cM), 5A (43–49, 56–60, 89–93 cM), 5B (124–125 cM), 6A (80–85 cM), and 6B (57–59, 71 cM). Among them, SNPs in chromosome 5A (89–93 cM) and 6A (80–85 cM) were co-located for yield and yield related traits. Overall, this study highlights the utility of SRIs as proxies for GY under YP and HS. High heritability estimates and identification of marker-trait associations indicate that SRIs are useful tools for understanding the genetic basis of agronomic and physiological traits.2019-01-01T00:00:00Z