7MYG

M. tb Ag85C modified by THL-10d

Summary for 7MYG

• Entry DOI: 10.2210/pdb7myg/pdb
• Descriptor: Diacylglycerol acyltransferase, GLYCEROL (3 entities in total)
• Functional Keywords: mycolyltransferase, alpha/beta-hydrolase fold, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 62478.93

Authors

Sudasinghe, T.D.,Ronning, D.R. (deposition date: 2021-05-21, release date: 2021-09-15, Last modification date: 2023-10-18)

Primary citation

Khan, S.S.,Sudasinghe, T.D.,Landgraf, A.D.,Ronning, D.R.,Sucheck, S.J.
Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species.
Acs Infect Dis., 7:2876-2888, 2021

PubMed Abstract: 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.

PubMed: 34478259
DOI: 10.1021/acsinfecdis.1c00283

Experimental method

X-RAY DIFFRACTION (2.51 Å)