7myg | pdb_00007myg
M. tb Ag85C modified by THL-10d
Structural highlights
FunctionA85C_MYCTU The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.[1] [2] Publication Abstract from PubMedTetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial alpha/beta hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis 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 alpha-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-beta-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two alpha/beta hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 +/- 22 muM) and Ag85C (66 +/- 8 muM), and its X-ray structure was solved in complex with Ag85C to 2.5 A resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 muM (25 mug/mL) and 16 muM (8.4 mug/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e 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 M. tuberculosis H37Ra was 65 mug/mL; however, the MIC was lowered to 0.25 mug/mL in the presence of 2.1 mug/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis. Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species.,Khan SS, Sudasinghe TD, Landgraf AD, Ronning DR, Sucheck SJ ACS Infect Dis. 2021 Sep 3. doi: 10.1021/acsinfecdis.1c00283. PMID:34478259[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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