Khan_2021_ACS.Infect.Dis_7_2876

Reference

Title : Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species - Khan_2021_ACS.Infect.Dis_7_2876
Author(s) : Khan SS , Sudasinghe TD , Landgraf AD , Ronning DR , Sucheck SJ
Ref : ACS Infect Dis , 7 :2876 , 2021
Abstract :

Tetrahydrolipstatin (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/Co(2)(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 microM) and Ag85C (66 +/- 8 microM), 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 microM (25 microg/mL) and 16 microM (8.4 microg/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 microg/mL; however, the MIC was lowered to 0.25 microg/mL in the presence of 2.1 microg/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.

PubMedSearch : Khan_2021_ACS.Infect.Dis_7_2876
PubMedID: 34478259
Gene_locus related to this paper: myctu-a85c

Related information

Inhibitor THL-10d    Orlistat
Substrate THL-10d    Orlistat    Orlistat
Gene_locus THL-10d    Orlistat    Orlistat    myctu-a85c
Structure THL-10d    Orlistat    Orlistat    myctu-a85c    7MYG

Citations formats

Khan SS, Sudasinghe TD, Landgraf AD, Ronning DR, Sucheck SJ (2021)
Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species
ACS Infect Dis 7 :2876

Khan SS, Sudasinghe TD, Landgraf AD, Ronning DR, Sucheck SJ (2021)
ACS Infect Dis 7 :2876