Beyond the ß-amino alcohols framework: identification of novel ß-hydroxy pyridinium salt-decorated pterostilbene derivatives as bacterial virulence factor inhibitors.

BACKGROUND: Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. RESULTS: A series of novel ß-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an half maximal effective concentration (EC50) value of 0.28 µg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analysis of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity: 71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. CONCLUSION: Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. © 2024 Society of Chemical Industry.

Identification of Novel Bisamide-Decorated Benzotriazole Derivatives as Anti-Phytopathogenic Virus Agents: Bioactivity Evaluation and Computational Simulation.

As a notorious phytopathogenic virus, the tobacco mosaic virus (TMV) severely reduced the quality of crops worldwide and caused critical constraints on agricultural production. The development of novel virucides is a persuasive strategy to address this predicament. Herein, a series of novel bisamide-decorated benzotriazole derivatives were elaborately prepared and screened. Biological tests implied that the optimized compound 7d possessed the most brilliant antiviral inactive profile (EC50 = 157.6 µg/mL) and apparently surpassed that of commercial ribavirin (EC50 = 442.1 µg/mL) 2.8-fold. The preliminary antiviral mechanism was elaborately investigated via transmission electron microscopy, microscale thermophoresis (MST) determination, RT-qPCR, and Western blot analysis. The results showed that compound 7d blocked the assembly of TMV by binding with coat protein (Kd = 0.7 µM) and suppressed TMV coat protein gene expression and biosynthesis process. Computational simulations indicated that 7d displayed strong H-bonds and pi interactions with TMV coat protein, affording a lower binding energy (ΔGbind = -17.8 kcal/mol) compared with Ribavirin (ΔGbind = -10.7 kcal/mol). Overall, current results present a valuable perception of bisamide decorated benzotriazole derivatives with appreciably virustatic competence and should be profoundly developed as virucidal candidates in agrochemical.

Identification of natural Rutaecarpine as a potent tobacco mosaic virus (TMV) helicase candidate for managing intractable plant viral diseases.

BACKGROUND: Naturally occurring alkaloids are particularly suitable for use as pesticide precursors and further modifications due to their cost-effectiveness, unique mechanism of action, tolerable degradation, and environmental friendliness. The famous tobacco mosaic virus (TMV) is a persistent plant pathogenic virus that can parasitize many plants and severely reduce crop production. To treat TMV disease, TMV helicase acts as a crucial target by hydrolyzing adenosine triphosphate (ATP) to provide energy for double-stranded RNA unwinding. RESULTS: To seek novel framework alkaloid leads targeting TMV helicase, this work successfully established an efficient screening platform for TMV helicase inhibitors based on natural alkaloids. In vivo activity screening, enzyme activity detection, and binding assays showed that Rutaecarpine from Evodia rutaecarpa (Juss.) Benth exhibited excellent TMV helicase inhibitory properties [dissociation constant (Kd ) = 1.1 µm, half maximal inhibitory concentration (IC50 ) = 227.24 µm] and excellent anti-TMV ability. Molecular docking and dynamic simulations depicted that Rutaecarpine could stably bind in active pockets of helicase with low binding energy (ΔGbind = -17.8 kcal/mol) driven by hydrogen bonding and hydrophobic interactions. CONCLUSION: Given Rutaecarpine's laudable bioactivity and structural modifiability, it can serve as a privileged building block for further pesticide discovery.

Novel Benzothiazole Derivatives as Potential Anti-Quorum Sensing Agents for Managing Plant Bacterial Diseases: Synthesis, Antibacterial Activity Assessment, and SAR Study.

As quorum sensing (QS) regulates bacterial pathogenicity, antiquorum sensing agents have powerful application potential for controlling bacterial infections and overcoming pesticide/drug resistance. Identifying anti-QS agents thus represents a promising approach in agrochemical development. In this study, the anti-QS potency of 53 newly prepared benzothiazole derivatives containing an isopropanolamine moiety was analyzed, and structure-activity relationships were examined. Compound D3 exhibited the strongest antibacterial activity, with an in vitro EC50 of 1.54 µg mL-1 against Xanthomonas oryzae pv oryzae (Xoo). Compound D3 suppressed QS-regulated virulence factors (e.g., biofilm, extracellular polysaccharides, extracellular enzymes, and flagella) to inhibit bacterial infection. In vivo anti-Xoo assays indicated good control efficiency (curative activity, 47.8%; protective activity, 48.7%) at 200 µg mL-1. Greater control efficiency was achieved with addition of 0.1% organic silicone or orange peel essential oil. The remarkable anti-QS potency of these benzothiazole derivatives could facilitate further novel bactericidal compound development.

Natural Products-Based Botanical Bactericides Discovery: Novel Abietic Acid Derivatives as Anti-Virulence Agents for Plant Disease Management.

The discovery of natural product-based pesticides is critical for agriculture. In this work, a series of novel tricyclic diterpenoid derivatives decorated with an amino alcohol moiety were elaborately prepared from natural abietic acid, and their antibacterial behavior was explored. Bioassay results indicated that compound C2 exhibited the most promising bioactivity (EC50 = 0.555 µg mL-1) against Xanthomonas oryzae pv. oryzae (Xoo), about 73 times higher than the effect of commercial thiodiazole copper (TC). Results of in vivo bioassays showed that compound C2 displayed significantly higher control of rice bacterial leaf blight (curative activity: 63.8%; protective activity: 58.4%) than TC (curative activity: 43.6%; protective activity: 40.8%), and their bioactivity could be improved maximally 16% by supplementing the auxiliaries. Antibacterial behavior suggested that compound C2 could suppress various virulence factors. Overall, these findings suggested that new botanical bactericide candidates could control intractable plant bacterial diseases by suppressing virulence factors.

New Inspiration of 1,3,4-Oxadiazole Agrochemical Candidates: Manipulation of a Type III Secretion System-Induced Bacterial Starvation Mechanism to Prevent Plant Bacterial Diseases.

Discovering new anti-virulent agents to control plant bacterial diseases by preventing bacterial pathogenesis/pathogenicity rather than affecting bacterial growth is a sensible strategy. However, the effects of compound-manipulated bacterial virulence factors on host response are still not clear. In this work, 35 new 1,3,4-oxadiazole derivatives were synthesized and systematically evaluated for their anti-phytopathogenic activities. Bioassay results revealed that compound C7 possessed outstanding antibacterial activity in vitro (half-maximal effective concentration: 0.80 µg/mL) against Xanthomonas oryzae pv. oryzae (Xoo) and acceptable bioactivity in vivo toward rice bacterial leaf blight. Furthermore, virulence factor-related biochemical assays showed that C7 was a promising anti-virulent agent. Interestingly, C7 could indirectly reduce the inducible expression of host SWEET genes and thereby alleviate nutrient supply in the infection process of phytopathogenic bacteria. Our results highlight the potential of 1,3,4-oxadiazole-based agrochemicals for manipulating type III secretion system-induced phytopathogenic bacteria starvation mechanisms to prevent plant bacterial diseases.

Novel spiro[chromanone-2,4'-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation.

Bacterial survival depends on membrane lipid homeostasis that enables to regulate lipid composition to adapt and optimize their growth in diverse environments. Therefore, the development of inhibitors that interfere with the bacterial fatty acid synthesis process is considered to be a promising tactic. In this study, 58 novel spirochromanone derivatives were prepared and their structure-activity relationship (SAR) was investigated. The bioassay results showed that all most of the compounds showed excellent biological activities, exampled by compounds B14, C1, B15, and B13, which had outstanding inhibitory activities toward various pathogenic bacteria with EC50 values of 0.78 µg/mL ∼3.48 µg/mL. Preliminary antibacterial behavior was studied by a series of biochemical assays including, but not limited to, fluorescence imaging patterns, GC-MS analysis, TEM images, and fluorescence titration experiments. Notably, compound B14 decreased the lipid content of the cell membrane, and increased cell membrane permeability, thereby destroying the integrity of the bacterial cell membrane. Further qRT-PCR results indicated that compound B14 interfered with the mRNA expression levels of fatty acid synthesis process-related genes including ACC, ACP, and Fab family genes. Herein, we highlight the promising bactericidal skeleton based on the spiro[chromanone-2,4'-piperidine]-4-one as a potential inhibitor of fatty acid synthesis.

Fabrication of Isopropanolamine-Decorated Coumarin Derivatives as Novel Quorum Sensing Inhibitors to Suppress Plant Bacterial Disease.

Emerging pesticide-resistant phytopathogenic bacteria have become a stumbling block in the development and use of pesticides. Quorum sensing (QS) blockers, which interfere with bacterial virulence gene expression, are a compelling way to manage plant bacterial disease without resistance. Herein, a series of isopropanolamine-decorated coumarin derivatives were designed and synthesized, and their potency in interfering with QS was investigated. Notably, compound A5 exhibited a better bioactivity with median effective concentration (EC50) values of 6.75 mg L-1 against Xanthomonas oryzae pv. oryzae (Xoo) than bismerthiazol (EC50 = 21.9 mg L-1). Further biochemical studies revealed that compound A5 disturbed biofilm formation and suppressed bacterial virulence factors and so forth. Moreover, compound A5 decreased the expression of QS-related genes. Interestingly, compound A5 had the acceptable control effect (53.2%) toward Xoo in vivo. Overall, this study identifies a novel lead compound for the development of bactericide candidates to control plant bacterial diseases by interfering with QS.

Exploring an Innovative Strategy for Suppressing Bacterial Plant Disease: Excavated Novel Isopropanolamine-Tailored Pterostilbene Derivatives as Potential Antibiofilm Agents.

Bacterial biofilms are the root cause of persistent and chronic phytopathogenic bacterial infections. Therefore, developing novel agrochemicals that target the biofilm of phytopathogenic bacteria has been regarded as an innovative tactic to suppress their invasive infection or decrease bacterial drug resistance. In this study, a series of natural pterostilbene (PTE) derivatives were designed, and their antibacterial potency and antibiofilm ability were assessed. Notably, compound C1 displayed excellent antibacterial potency in vitro, affording an EC50 value of 0.88 µg mL-1 against Xoo (Xanthomonas oryzae pv. oryzae). C1 could significantly reduce biofilm formation and extracellular polysaccharides (EPS). Furthermore, C1 also possessed remarkable inhibitory activity against bacterial extracellular enzymes, pathogenicity, and other virulence factors. Subsequently, pathogenicity experiments were further conducted to verify the above primary outcomes. More importantly, C1 with pesticide additives displayed excellent control efficiency. Given these promising profiles, these pterostilbene derivatives can serve as novel antibiofilm agents to suppress plant pathogenic bacteria.

Assembling Anthracene-Tailored Amphiphiles: Charge-Transfer Interactions Directed Hierarchical Nanofibers with Ameliorative Antibacterial Activity toward Plant Pathogens.

The effective prevention of plant bacterial infections has been complicated and challenged by unceasing bacterial resistance. The application of traditional bactericides has achieved certain effects to alleviate this situation. However, these chemicals also have limitations, such as short half-life in reality, limited bioavailability, and pollutant emission from their formulations. These disadvantages drive the demand for promoting antibacterial therapeutics. Self-assembled nanostructures based on amphiphiles have inherently versatile characteristics, including high durability, good bioavailability, sustained release, and regenerability. As such, they have garnered wide interest because of these advantages that may serve as a feasible platform for the management of pathogenic infections. Flexible tuning of the shapes of these nanostructures by manipulating noncovalent driving forces consequently results in different levels of antibacterial activity. Herein, an antibacterial amphiphile, 1-[11-(9-anthracenylmethoxy)-11-oxoundecyl]pyridinium bromide (AP), was assembled into microfilms in screening medium. Hierarchical nanofibers were constructed by introducing an electron-deficient trinitrofluorenone (TNF) molecule into the assembling system directed by charge-transfer (CT) interactions to further investigate the contribution of aggregate shape to bioactivity. Biological evaluation revealed that antibacterial efficacy improved after CT complex formation. This study provides an innovative platform for developing versatile assembled structures for restraining the propagation of plant pathogens and an improved understanding of the actual interplay between the self-assembly and antibacterial ability of bactericides at the supramolecular level.