Discovery of Polycyclic Polyprenylated Acylphloroglucinols from Hypericum androsaemum as Dual-Mechanism Inhibitors of Mycobacterium tuberculosis GlmU Acetyltransferase.

(±)-Hypericandrone A (HCA, 1), an unprecedented pair of enantiomeric polycyclic polyprenylated acylphloroglucinols (PPAPs), and its biosynthetic congener hypericandrone B (HCB, 2) were isolated from the fruits of Hypericum androsaemum. Compound 1 features a unique 2-cyclopentane-bicyclo[3.3.0]octane scaffold, while 2 possesses a rare 2-cyclopentyltetrahydrofuran framework. Their absolute configurations were unequivocally determined by spectroscopic analysis, single-crystal X-ray diffraction, and ECD calculations. Remarkably, (+)-1 displayed potent antitubercular activity by selectively inhibiting the acetyltransferase domain of Mycobacterium tuberculosis GlmU through a dual mechanism, acting competitively against acetyl-CoA (Ki = 0.07 μM) and noncompetitively against glucosamine-1-phosphate (GlcN-1-P, Ki = 0.20 μM).