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.

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.

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.

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.

1,3,4-Oxadiazole Derivatives as Plant Activators for Controlling Plant Viral Diseases: Preparation and Assessment of the Effect of Auxiliaries.

Plant viral diseases cause the loss of millions of dollars to agriculture around the world annually. Therefore, the development of highly efficient, ultra-low-dosage agrochemicals is desirable for protecting the health of crops and ensuring food security. Herein, a series of 1,3,4-oxadiazole derivatives bearing an isopropanol amine moiety was prepared, and the inhibitory activity against tobacco mosaic virus (TMV) was assessed. Notably, compound A14 exhibited excellent anti-TMV protective activity with an EC50 value of 137.7 mg L-1, which was superior to that of ribavirin (590.0 mg L-1) and ningnanmycin (248.2 mg L-1). Moreover, the anti-TMV activity of some compounds could be further enhanced (by up to 5-30%) through supplementation with 0.1% auxiliaries. Biochemical assays suggested that compound A14 could suppress the biosynthesis of TMV and induce the plant's defense response. Given these merits, designed compounds had outstanding bioactivities and unusual action mechanisms and were promising candidates for controlling plant viral diseases.

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.

Synthesis and Biological Evaluation of 1,2,4-Triazole Thioethers as Both Potential Virulence Factor Inhibitors against Plant Bacterial Diseases and Agricultural Antiviral Agents against Tobacco Mosaic Virus Infections.

Targeting the virulence factors of phytopathogenic bacteria is an innovative strategy for alleviating or eliminating the pathogenicity and rapid outbreak of plant microbial diseases. Therefore, several types of 1,2,4-triazole thioethers bearing an amide linkage were prepared and screened to develop virulence factor inhibitors. Besides, the 1,2,4-triazole scaffold was exchanged by a versatile 1,3,4-oxadiazole core to expand molecular diversity. Bioassay results revealed that a 1,2,4-triazole thioether A10 bearing a privileged N-(3-nitrophenyl)acetamide fragment was extremely bioactive against Xanthomonas oryzae pv. oryzae (Xoo) with an EC50 value of 5.01 µg/mL. Label-free quantitative proteomics found that compound A10 could significantly downregulate the expression of Xoo's type III secretion system (T3SS) and transcription activator-like effector (TALE) correlative proteins. Meanwhile, qRT-PCR detection revealed that the corresponding gene transcription levels of these virulence factor-associated proteins were substantially inhibited after being triggered by compound A10. As a result, the hypersensitive response and pathogenicity were strongly depressed, indicating that a novel virulence factor inhibitor (A10) was probably discovered. In vivo anti-Xoo trials displayed that compound A10 yielded practicable control efficiency (54.2-59.6%), which was superior to thiadiazole-copper and bismerthiazol (38.1-44.9%). Additionally, compound A10 showed an appreciable antiviral activity toward tobacco mosaic virus (TMV) with the curative and protective activities of 54.6 and 76.4%, respectively, which were comparable to ningnanmycin (55.2 and 60.9%). This effect was further validated and visualized by the inoculation test using GFP-labeled TMV, thereby leading to the reduced biosynthesis of green-fluorescent TMV on Nicotiana benthamiana. Given the outstanding features of compound A10, it should be deeply developed as a versatile agricultural chemical.

Rational Optimization of 1,2,3-Triazole-Tailored Carbazoles As Prospective Antibacterial Alternatives with Significant In Vivo Control Efficiency and Unique Mode of Action.

Plant bacterial diseases can potentially damage agricultural products around the world, and few effective bactericides can manage these infections. Herein, to sequentially explore highly effective antibacterial alternatives, 1,2,3-triazole-tailored carbazoles were rationally fabricated. These compounds could suppress the growth of three main intractable pathogens including Xanthomonas oryzae pv oryzae (Xoo), X. axonopodis pv citri (Xac), and Pseudomonas syringae pv actinidiae (Psa) with lower EC50 values of 3.36 (3p), 2.87 (3p), and 4.57 µg/mL (3r), respectively. Pot experiments revealed that compound 3p could control the rice bacterial blight with protective and curative efficiencies of 53.23% and 50.78% at 200 µg/mL, respectively. Interestingly, the addition of 0.1% auxiliaries such as organic silicon and orange oil could significantly enhance the surface wettability of compound 3p toward rice leaves, resulting in improved control effectiveness of 65.50% and 61.38%, respectively. Meanwhile, compound 3r could clearly reduce the white pyogenic exudates triggered by Psa infection and afforded excellent control efficiencies of 79.42% (protective activity) and 78.74% (curative activity) at 200 µg/mL, which were quite better than those of commercial pesticide thiodiazole copper. Additionally, a plausible apoptosis mechanism for the antibacterial behavior of target compounds was proposed by flow cytometry, reactive oxygen species detection, and defensive enzyme (e.g., catalase and superoxide dismutase) activity assays. The current work can promote the development of 1,2,3-triazole-tailored carbazoles as prospective antibacterial alternatives bearing an intriguing mode of action.

Synthesis and Docking Study of N-(Cinnamoyl)-N'-(substituted)acryloyl Hydrazide Derivatives Containing Pyridinium Moieties as a Novel Class of Filamentous Temperature-Sensitive Protein Z Inhibitors against the Intractable Xanthomonas oryzae pv. oryzae Infections in Rice.

Xanthomonas oryzae pv. oryzae (Xoo) is an offensive phytopathogen that can invade a wide range of plant hosts to develop bacterial diseases, including the well-known rice bacterial leaf blight. However, few agrochemicals have been identified to effectively prevent and eliminate Xoo-induced diseases. Thus, designing novel antibacterial compounds on the basis of the potential targets from Xoo may lead to the discovery of highly efficient and innovative anti-Xoo agents. Filamentous temperature-sensitive protein Z (FtsZ), an important functional protein in the progression of cell division, has been widely reported and exploited as a target for creating antibacterial drugs in the field of medicine. Therefore, the fabrication of innovative frameworks targeting XooFtsZ may be an effective method for managing bacterial leaf blight diseases via blocking the binary division and reproduction of Xoo. As such, a series of novel N-(cinnamoyl)-N'-(substituted)acryloyl hydrazide derivatives containing pyridinium moieties were designed, and the anti-Xoo activity was determined. The bioassay results showed that compound A7 had excellent anti-Xoo activity (EC50 = 0.99 mg L-1) in vitro and distinct curative activity (63.2% at 200 mg L-1) in vivo. Further studies revealed that these designed compounds were XooFtsZ inhibitors, validating by the reduced GTPase activity of recombinant XooFtsZ, the nonfilamentous XooFtsZ assembly observed in the TEM images, and the prolonged Xoo cells from the fluorescence patterns. Computational docking studies showed that compound A7 had strong interactions with ASN34, GLN193, and GLN197 residues located in the α helix regions of XooFtsZ. The present study demonstrates the developed FtsZ inhibitors can serve as agents to control Xoo-induced infections.

Antibacterial activities against Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae of 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives.

In this letter, a variety of simple 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives was prepared. Preliminary bioassays revealed that these compounds showed good antibacterial activities toward phytopathogens Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae (Xoo). Among these derivatives, compounds 5a, 5d, 5e, 5f, 5p, 5q, 6b, and 6d exhibited potent inhibition effects against R. solanacearum with EC50 within 4.60-9.94 µg/mL, especially, compound 5g exerted the strongest activity with EC50 of 2.72 µg/mL; compound 6b possessed the best inhibitory activity toward Xoo with EC50 of 8.46 µg/mL. Subsequently, a good predictive three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed via CoMFA to direct the future structural modification and optimization. Furthermore, the pathogens' topological studies were performed to explore the possible antibacterial mechanism. Given their simple frameworks and facile synthesis, title compounds can serve as the potential antibacterial leads.