| Summary: | Eicosanoids mediate both cellular and humoral immune responses in insects. Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) catalyzes the first committed step in eicosanoid biosynthesis. It is a common pathogenic target of two entomopathogenic bacteria, <i>Xenorhabdus</i> and <i>Photorhabdus</i>. The objective of this study was to identify novel PLA<sub>2</sub> inhibitors from <i>X. hominickii</i> and determine their immunosuppressive activities. To identify novel PLA<sub>2</sub> inhibitors, stepwise fractionation of <i>X. hominickii</i> culture broth and subsequent enzyme assays were performed. Eight purified fractions of bacterial metabolites were obtained. Gas chromatography and mass spectrometry (GC-MS) analysis predicted that the main components in these eight fractions were 2-cyanobenzoic acid, dibutylamine, 2-ethyl 1-hexanol, phthalimide (PM), dioctyl terephthalate, docosane, bis (2-ethylhexyl) phthalate, and 3-ethoxy-4-methoxyphenol (EMP). Their synthetic compounds inhibited the activity of PLA<sub>2</sub> in hemocytes of a lepidopteran insect, <i>Spodoptera exigua</i>, in a dose-dependent manner. They also showed significant inhibitory activities against immune responses such as prophenoloxidase activation and hemocytic nodulation of <i>S. exigua</i> larvae, with PM and EMP exhibiting the most potent inhibitory activities. These immunosuppressive activities were specific through PLA<sub>2</sub> inhibition because an addition of arachidonic acid, a catalytic product of PLA<sub>2</sub>, significantly rescued such suppressed immune responses. The two most potent compounds (PM and EMP) showed significant insecticidal activities after oral administration. When the compounds were mixed with <i>Bacillus thuringiensis</i> (Bt), they markedly increased Bt pathogenicity. This study identified eight PLA<sub>2</sub> inhibitors from bacterial metabolites of <i>X. hominickii</i> and demonstrated their potential as novel insecticides.
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