Background/Objectives: Marine microorganism metabolites are structurally unique secondary metabolites possessing therapeutic potential. The current study aims to identify a novel ATPase regulator using a newly established bidirectional activity evaluation system to screen for microbial metabolites that inhibit the activities of Na⁺-K⁺-ATPase or Ca²⁺-Mg²⁺-ATPase. Methods: A total of 1258 marine microbial strains were isolated from sea mud in Zhoushan, Zhejiang. Results: The extract of strain ZSDH2536 exhibited Na⁺-K⁺ and Ca²⁺-Mg²⁺-ATPase inhibitory activity and was identified as Sirastachys pandanicola based on morphological and molecular phylogenetic analyses. The secondary metabolite was tentatively identified in the ZSDH2536 strain as a bisindole compound, and named Pandanicoline based on ¹H-NMR, ¹³C-NMR and high-resolution mass spectrometry analysis. The chemical formula of Pandanicoline is C₅₁H₆₈N₂O₁₀, with an isotopic mass of 868.4874 Da. The maximum inhibition rate of Pandanicoline on Na⁺-K⁺ and Ca²⁺-Mg²⁺-ATPase was 36.37% and 37.27%, respectively. Moreover, in silico analysis also showed the binding energy of Pandanicoline with Na⁺-K⁺-ATPase was −9.124 kcal/mol and with the Ca²⁺-Mg²⁺-ATPase complex was −10.47 kcal/mol. Conclusions: The strain ZSDH2536 represents a promising source of dual inhibitors targeting Na⁺-K⁺ and Ca²⁺-Mg²⁺-ATPase. Pandanicoline exhibits potential as a lead compound for regulating ion homeostasis, providing new opportunities for further investigation into its mechanism and therapeutic applications.

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