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Natural products containing the highly unusual phosphotriester ring are known to be potent serine hydrolase inhibitors. The long-chain bicyclic enol-phosphotriester salinipostins (SPTs) from the marine actinomycete Salinispora have been identified as selective antimalarial agents. A potential regulatory function has been suggested for phosphotriesters based on their structural relationship with actinomycete signaling molecules and the prevalence of spt -like biosynthetic gene clusters across actinomycetes. In this study, we established a mass spectrometry-guided screening method for phosphotriesters focusing on their characteristic fragment ions. Applying this screening method to the SPT producer Salinispora tropica CNB-440, new SPT analogs (4 - 6) were discovered and their structures were elucidated by spectroscopic analyses. Previously known and herein-identified SPT analogs inhibited the activity of human monoacylglycerol lipase (MAGL), a key serine hydrolase in the endocannabinoid system, in the nanomolar range. Our method could be applied to the screening of phosphotriesters, potential serine hydrolase inhibitors and signaling molecules. [ABSTRACT FROM AUTHOR]