Cheminformatics and artificial intelligence for accelerating agrochemical discovery.

The global cost-benefit analysis of pesticide use during the last 30 years has been characterized by a significant increase during the period from 1990 to 2007 followed by a decline. This observation can be attributed to several factors including, but not limited to, pest resistance, lack of novelty with respect to modes of action or classes of chemistry, and regulatory action. Due to current and projected increases of the global population, it is evident that the demand for food, and consequently, the usage of pesticides to improve yields will increase. Addressing these challenges and needs while promoting new crop protection agents through an increasingly stringent regulatory landscape requires the development and integration of infrastructures for innovative, cost- and time-effective discovery and development of novel and sustainable molecules. Significant advances in artificial intelligence (AI) and cheminformatics over the last two decades have improved the decision-making power of research scientists in the discovery of bioactive molecules. AI- and cheminformatics-driven molecule discovery offers the opportunity of moving experiments from the greenhouse to a virtual environment where thousands to billions of molecules can be investigated at a rapid pace, providing unbiased hypothesis for lead generation, optimization, and effective suggestions for compound synthesis and testing. To date, this is illustrated to a far lesser extent in the publicly available agrochemical research literature compared to drug discovery. In this review, we provide an overview of the crop protection discovery pipeline and how traditional, cheminformatics, and AI technologies can help to address the needs and challenges of agrochemical discovery towards rapidly developing novel and more sustainable products.

Dicamba resistance in kochia from Kansas and Nebraska evolved independently.

BACKGROUND: Evolution and spread of resistance to glyphosate in kochia [Bassia scoparia (L.) A.J. Scott] is a major challenge for the sustainability of glyphosate-resistant crop technology in this region. Dicamba offers a viable option to manage glyphosate-resistant kochia. However, the recent and rapid evolution of dicamba resistance in glyphosate-resistant kochia populations in Kansas (KS), and other states in the USA is a threat to the management of this weed. Our previous research suggests that two distinct mechanisms confer dicamba resistance in KS (KSUR) and NE (CSUR) kochia. CSUR kochia is dicamba-resistant due to a double mutation in an auxin and dicamba coreceptor gene (Aux/IAA16), and CSUR kochia plants show reduced dicamba translocation. However, the mechanism of dicamba resistance in KSUR is not known. The objective of this research was to determine if dicamba resistance in KSUR is due to a different mechanism and therefore evolved independently from CSUR by measuring whether the resistance traits are chromosomally linked. RESULTS: The F1 and F2 progenies from KSUR × CSUR were generated. Single dicamba rate tests were conducted using the F1 and F2 progeny. The results indicate that two different genes confer dicamba resistance in KSUR and CSUR; importantly, these two genes are not linked. CONCLUSION: This research provides evidence that different populations of kochia have independently evolved resistance to dicamba by different mechanisms, and we confirmed that the genes conferring resistance to the same herbicide in different populations are not chromosomally linked.

Reduced Translocation of Glyphosate and Dicamba in Combination Contributes to Poor Control of Kochia scoparia: Evidence of Herbicide Antagonism.

Kochia scoparia is a troublesome weed across the Great Plains of North America. Glyphosate and dicamba have been used for decades to control K. scoparia. Due to extensive selection, glyphosate- and dicamba-resistant (GDR) K. scoparia have evolved in the USA. Herbicide mixtures are routinely used to improve weed control. Herbicide interactions if result in an antagonistic effect can significantly affect the management of weeds, such as K. scoparia. To uncover the interaction of glyphosate and dicamba when applied in combination in K. scoparia management the efficacies of different doses of glyphosate plus dicamba were evaluated under greenhouse and field conditions using GDR and a known glyphosate- and dicamba-susceptible (GDS) K. scoparia. The results of greenhouse and field studies suggest that the combination of glyphosate and dicamba application controlled GDS, but glyphosate alone provided a better control of GDR K. scoparia compared to glyphosate plus dicamba combinations. Furthermore, investigation of the basis of this response suggested glyphosate and dicamba interact antagonistically and consequently, the translocation of both herbicides was significantly reduced resulting in poor control of K. scoparia. Therefore, a combination of glyphosate plus dicamba may not be a viable option to control GDR K. scoparia.

Pleiotropic roles of Clostridium difficile sin locus.

Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR', coding for SinR (112 aa) and SinR' (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus's role in C. difficile physiology. Transcriptome analysis of the sinRR' mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR' acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis.

Reduced absorption of glyphosate and decreased translocation of dicamba contribute to poor control of kochia (Kochia scoparia) at high temperature.

BACKGROUND: Plant growth temperature is one of the important factors that can influence postemergent herbicide efficacy and impact weed control. Control of kochia (Kochia scoparia), a major broadleaf weed throughout the North American Great Plains, often is unsatisfactory when either glyphosate or dicamba are applied on hot summer days. We tested effects of plant growth temperature on glyphosate and dicamba phytotoxicity on two Kansas kochia populations (P1 and P2) grown under the following three day/night (d/n) temperature regimes: T1, 17.5/7.5°C; T2, 25/15°C; and T3, 32.5/22.5°C. RESULTS: Visual injury and above-ground dry biomass data from herbicide dose-response experiments indicated greater susceptibility to both glyphosate and dicamba when kochia was grown under the two cooler temperature regimes, i.e. T1 and T2. At T1, the ED50 of P1 and P2 kochia were 39 and 36 g ha-1 of glyphosate and 52 and 105 g ha-1 of dicamba, respectively. In comparison, at T3 the ED50 increased to 173 and 186 g ha-1 for glyphosate and 106 and 410 g ha-1 for dicamba, respectively, for P1 and P2. We also investigated the physiological basis of decreased glyphosate and dicamba efficacy under elevated temperatures. Kochia absorbed more glyphosate at T1 and T2 compared to T3. Conversely, there was more dicamba translocated towards meristems at T1 and T2, compared to T3. CONCLUSION: Reduced efficacy of dicamba or glyphosate to control kochia under elevated temperatures can be attributed to decreased absorption and translocation of glyphosate and dicamba, respectively. Therefore, it is recommended to apply glyphosate or dicamba when the temperature is low (e.g. d/n temperature at 25/15°C) and seedlings are small (less than 12 cm) to maximize kochia control. © 2016 Society of Chemical Industry.

Increased chalcone synthase (CHS) expression is associated with dicamba resistance in Kochia scoparia.

BACKGROUND: Resistance to the synthetic auxin herbicide dicamba is increasingly problematic in Kochia scoparia. The resistance mechanism in an inbred dicamba-resistant K. scoparia line (9425R) was investigated using physiological and transcriptomics (RNA-Seq) approaches. RESULTS: No differences were found in dicamba absorption or metabolism between 9425R and a dicamba-susceptible line, but 9425R was found to have significantly reduced dicamba translocation. Known auxin-responsive genes ACC synthase (ACS) and indole-3-acetic acid amino synthetase (GH3) were transcriptionally induced following dicamba treatment in dicamba-susceptible K. scoparia but not in 9425R. Chalcone synthase (CHS), the gene regulating synthesis of the flavonols quertecin and kaemperfol, was found to have twofold higher transcription in 9425R both without and 12 h after dicamba treatment. Increased CHS transcription co-segregated with dicamba resistance in a forward genetics screen using an F2 population. CONCLUSION: Prior work has shown that the flavonols quertecin and kaemperfol compete with auxin for intercellular movement and vascular loading via ATP-binding cassette subfamily B (ABCB) membrane transporters. The results of this study support a model in which constitutively increased CHS expression in the meristem produces more flavonols that would compete with dicamba for intercellular transport by ABCB transporters, resulting in reduced dicamba translocation. © 2017 Society of Chemical Industry.

Development of a monoclonal antibody-based enzyme-linked immunosorbent assay for tetrabromobisphenol A.

Tetrabromobisphenol A (TBBPA) has been an important brominated flame retardant worldwide and has become a widely concerned environmental pollutant due to its persistence in the environment. In this study, a monoclonal antibody (MAb, designated 3D9G6) against TBBPA was produced, and an indirect competitive enzyme-linked immunoassay (icELISA) for detecting trace TBBPA was developed. The limit of detection and the half maximum inhibition concentration of TBBPA in phosphate-buffered saline were 0.8 and 3.87 ng·mL(-1), respectively. The assay specificity was studied with TBBPA structural analogs, such as bisphenol A, decabromodiphenyl ether, octabromobisphenol-S, and hexabromocyclododecane, and the results showed that none of these can be recognized by the MAb even at a concentration of up to 4000 ng·mL(-1). The average recoveries of TBBPA in water and soil samples were 96% and 87%, respectively. This icELISA can be applied for the detection of trace levels of TBBPA in water and soil samples.

Synthesis and bioactivity study of 2-acylamino-substituted N'-benzylbenzohydrazide derivatives.

The discovery of new safe and effective pesticides is one of the main means of providing eco-friendly agricultural agents for modern crop protection. To identify new biological molecules based of the anthranilic diamide skeleton of the novel pesticide chlorantraniliprole, which acts on the ryanodine receptor and functional groups in acyl hydrazine insect growth regulators, more than 40 new compounds of 2-acylamino-substituted N'-benzylbenzohydrazide derivatives were designed and synthesized. The structures of the new compounds were characterized using (1)H nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), or electron impact mass spectrometry (EI-MS), and their biological activities at a concentration of 600 mg L(-1) were determined against cotton aphid (Aphis gossypii Glover), carmine spider mite (Tetranychus cinnabarinus), and diamondback moth (Plutella xylostella). The results of a preliminary assay showed that compounds 6a-I-2 and 6d-III-4 maintained the lethal activity of anthranilic diamide against P. xylostella; compounds 6c-II-4, 6d-I-7, 6d-II-1, and 6d-III-5 exhibited good lethal activity against A. gossypii; and compounds 6a-II-1, 6a-III-1, 6b-I-7, 6c-I-1, and 6c-III-5 retained promising larvicidal activities against T. cinnabarinus. In subsequent further tests against T. cinnabarinus, compounds 6a-II-1, 6a-III-1, 6c-I-1, and 6c-III-5 showed an LC(50) value of <90 mg L(-1); especially, the LC(50) of compound 6a-III-1 was only 27.9 mg L(-1). In conclusion, the introduction of the functional fragment-substituted acyl hydrazine improved the acaricidal activity of the anthranilic diamide skeleton, and the halogen atom at X position and the methyl group at R(1) play crucial roles in the biological activities of the compounds.

Impact of halogen substituents on interactions between 2-phenyl-2,3-dihydroqulinazolin-4(1H)-one derivatives and human serum albumin.

A novel type of 2-(un)substituted phenyl-2,3-dihydroquinazolin-4(1H)-one (DQL) derivatives were designed and synthesized to study the impact of halogen substituents on interactions between DQL and human serum albumin (HSA) by comparison methodology. The interactions between DQL and HSA were studied by fluorescence spectroscopy. The intrinsic fluorescence of human serum albumin was quenched by DQL through a static quenching mechanism. Site marker competitive experiments showed that DQL bound to HSA in site II (subdomain IIIA). The binding constants, the numbers of binding sites and the thermodynamic parameters were measured too. The results indicated that the interactions were spontaneous, mainly through hydrophobic forces, and the substitution by halogen atoms in the benzene ring could increase the interactions between DQL and HSA. Furthermore, the binding affinity was enhanced gradually with the increasing of halogen atomic number.