Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Species
Article (Faculty180)
Khan, Saniya S S; Sudasinghe, Thanuja D; Landgraf, Alexan D; Ronning, Donald R; Sucheck, Steven J
description
Tetrahydrolipstatin (THL, ) has been shown to inhibit both mammalian and bacterial α/β hydrolases. In the case of bacterial systems, THL is a known inhibitor of several hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL α-chain substituent to afford compounds through . The key transformation in the synthesis was use of a (TPP)CrCl/Co(CO)-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a -β-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two α/β hydrolases of involved in the biosynthesis of the mycomembrane. Among these compounds, showed the highest inhibitory effect on Ag85A (34 ± 22 μM) and Ag85C (66 ± 8 μM), and its X-ray structure was solved in complex with Ag85C to 2.5 Å resolution. In contrast, compound exhibited the best-in-class MICs of 50 μM (25 μg/mL) and 16 μM (8.4 μg/mL) against . and H37Ra, respectively, using a microtiter assay plate. Combination of with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in . and H37Ra. Compound applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against H37Ra was 65 μg/mL; however, the MIC was lowered to 0.25 μg/mL in the presence of 2.1 μg/mL demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.